Tricyclic nitrogen ring compounds, their production and use

ABSTRACT

Tricyclic compound of the formula: ##STR1## wherein ring A is a nitrogen-containing heterocyclic ring, having two nitrogen atoms as the hetero-atoms, which is optionally substituted with oxo or thioxo; ring Q may optionally be substituted; Y is an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted mecapto group, excluding for methyl group as Y; R 1  is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, or a salt thereof, having excellent PDGF-inhibiting activities, antihypertensive activities, activities of ameliorating renal diseases and activities of lowering lipid level.

This application is a continuation-in-part of Ser. No. 08/500,945 filedAug. 7, 1995, which was a §371 application of PCT/JP95/01382 filed Jul.12, 1995.

TECHNICAL FIELD

The present invention relates to a novel tricyclic compound, which isuseful as a medicine having an excellent activity of inhibitingplatelet-derived growth factor (PDGF), antihypertensive activity,ameliorating activity of renal diseases and lowering the cholesterollevel, a process for producing the compound, and a pharmaceuticalcomposition containing the compound.

BACKGROUND ART

With the progressive increase of aged population in recent years,various ischemic diseases in cerebral and cardiac vessels have been alsoincreasing. As the therapeutic agents of these diseases, calcium channelblockers or angiotensin converting enzymes (ACE) inhibitors have beenwidely used in the clinical field and have served to decreasecerebrovascular disturbances due to hypertension. However, the mortalityfrom ischemic heart diseases has not yet been decreased. For improvingthem, it has been considered that lowering blood pressure is notsufficient but improving lipid metabolism is necessary. And, the degreeof antihypertensive action is important; namely, it has been consideredthat, the agents which keep the elasticity of blood vessels are morepreferable even if their antihypertensive action is milder than theagents which lower blood pressure markedly. For keeping the elasticityof blood vessels, it is necessary to positively improve vascularhypertrophy or fibrosis. As the diseases causing vascular hypertrophy,there are mentioned, for example, hypertension, diabetes,glomerulosclerosis (chronic renal failure) and arteriosclerosis.Precutaneous transliminal coronary angioplasty (PTCA) is generallycarried out in the case of coronary artery obstruction caused byplatelet aggregation and accumulation. In this case, however, there isoften observed that endothelium is injured to cause proliferation ofvascular smooth muscle toward the inside of vessels and to lead torestoerosis.

As one of the common phenomena observed in these diseases mentionedabove, the enhanced expression of platelet-derived growth factor (PDGF)or PDGF receptors (mRNA) has been reported.

More specifically stating; 1) In spontaneously hypertensive rats (SHR)and renal hypertensive animals, expression of PDGF or PDGF receptors isenhanced, or the tyrosine kinase activity associated with PDGF receptorsis enhanced (R. Sarzani et al., Hypertension, 18, III 93/1991; P.Pauletto et al., 15th International Meeting of Hypertension, Melbourne,Abstract 1197/1994; M. D. Sauro and B. Thomas, Life Sci., 53,PL371/1993). 2) In the essential hypertensive patients with diabetes, ithas been observed that blood concentration of PDGF in blood is higherthan normal subjects. (P. Bolli et al., 15th International Meeting ofHypertension, Melbourne, Abstract 767/1994). 3) In human atheroscleroticplaques, expression of PDGF mRNA is enhanced (T. Barrett and P. Benditt,Proc. Natl. Acad. Sci. USA, 85, 2810/1988; J. N. Wilcox et al., J. Clin.Invest., 82, 1134/1988), in the vascular smooth muscle cells of diabeticrats with arteriosclerosis, expression of PDGF receptors is enhanced (T.Kanzaki, Y. Saitoh, Gendai Iryo (Modern Therapeutics), 23, 2614/1991).4) In the blood vessels of balloon injured animals and humans afterPTCA, the expression of PDGF or PDGF receptor is enhanced (M. W. Majeskyet al., J. Cell Biol., 111, 2149/1990; M. Ueda et al., Circulation, 86(Suppl.), 1/1992). 5) In renal mesangial cells of 5/6 nephrectomizedrats, a model of focal glomerulosclerosis, expression of PDGF isenhanced (J. Floege et al., Kidney Int., 41, 297/1992). 6) In mesangiumproliferative nephritis (IgA nephropathy) and a model of nephritis inrats, enhancement of PDGF in mesangial cells is observed (R. J. Johnsonet al., J. Am. Soc. Nephrol., 4, 119/1993; H. E. Abboud et al., KidneyInt., 43, 252/1993). It is demonstrated that PDGF proliferates vascularsmooth muscle cells or renal glomerular mesangial cells in vitroexperiments (R. Ross et al., Cell, 46, 155/1986); J. Floege et al.,Clin. Exp. Immunol., 86, 334/1991) and in vivo experiments (A. Jawien etal., J. Clin. Invest., 89, 507/1992; Y. Isaka et al., J. Clin. Invest.,92 2597/1993; J. Floege et al., J. Clin. Invest., 92, 2952/1993). It isalso reported that the action of cytokine TGF-β (transforming growthfactor β) is via the action of PDGF expressed by TGF-β (E. G. Battegayet al., Cell, 63, 515/1990). Furthermore, recently there have been anumber of reports that hypertensive vascular hypertrophy and cardiachypertrophy due to congestive heart failure are suppressed byadministration of ACE inhibitors or angiotensin antagonistic agent. Itis considered that, also in the angiotensin-mediated vascularhypertrophy and cardiac hypertrophy, PDGF plays a role (A. J. Naftilanet al., J. Clin. Invest., 83, 1419/1989; G. H. Gibbons et al., J. Clin.Invest., 90, 456/1992). Besides, it has been known that, in respect ofthe proliferation of vascular smooth muscle cells or renal mesangialcells, LDL-cholesterol and PDGF mutually cooperate to enhance theproliferation, which has been considered as one of factors causingarteriosclerosis. Therefore, drugs capable of specifically inhibitingthe action of PDGF are expected to be useful therapeutic agents ofvarious circulatory disturbances including arteriosclerosis.

On the other hand, as the tricyclic compounds, the following compoundsare disclosed in the following literature references, namely, (1) J.Heterocycl. Chem., 1972, 9 (1), p.85, (2) J. Heterocycl. Chem., 1976, 13(5), p.1029-1031, (3) J. Mol. Struct., Perkin Trans.1, 1978, 49 (2),p415-420, (4) J. Pharm. Soc. Jpn., 1978, 98 (5) p.631-635, (5) J.Crystallogr. Spectrosc. Res., 1989, 19 (1), p.159-166, (6) Bull. Pol.Acad. Sci., Chem., 1989, 37 (7-8), p.313-316, and (7) J. Chem. Soc.,Perkin Trans. 1, 1987, (5), p.1159-1163. However, no reports concerningthe therapeutic uses of these compounds has been found yet.

    ______________________________________    Structural Formula    Symbol    ______________________________________     ##STR2##    1                     R.sup.1 = H or CH.sub.3 X = O or H.sub.2    2 #STR3##             R.sup.1 = H or CH.sub.3 R.sup.2 = H or CH.sub.3    3 #STR4##             R.sup.1 = SCH.sub.3 R.sup.2 = H or CH.sub.3    4 #STR5##    ______________________________________

DISCLOSURE OF INVENTION

Circumstances being such as above, the development of novel and safelyadministrable therapeutic agents has been desired, which inhibit theaction of PDGF.

The present inventors have made extensive and intensive studies, andsucceeded in synthesizing, for the first time, a compound of theformula: (I')(hereinafter called the compound (I')) ##STR6## whereinring A is a nitrogen-containing heterocyclic ring, having two nitrogenatoms as the hetero-atoms, which is optionally substituted with oxo orthioxo; ring Q may optionally be substituted;

Y is an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group or an optionally substituted mercapto group,excluding methyl group as Y; and

R¹ is a hydrogen atom, a halogen atom, an optionally substitutedhydrocarbon group or an acyl group, or a salt thereof, whosecharacteristic feature of the chemical structure lies in the tricycliccondensed heterocyclic ring of the formula: ##STR7## and the substituenton ring A, as the representative of the tricyclic condensed heterocyclicring wherein the three kinds of rings of the pyridine ring Q, theimidazole ring and the heterocyclic ring A containing nitrogen-atom arecondensed, comprising nitrogen-atom at the head of bridge in thecondensed ring, especially a compound of the formula (I) (hereinaftercalled the compound (I)): ##STR8## wherein ring A, ring Q and R¹ are asdefined above;

B is an optionally substituted divalent hydrocarbon;

X is a bond, an oxygen atom or a sulfur atom;

R² is a hydrogen atom or an optionally substituted hydrocarbon group or,R² and B may form a ring together with the adjacent nitrogen atom; and

R³ is an electron-withdrawing group, or a salt thereof, whosecharacteristic feature of the chemical structure lies in the tricycliccondensed heterocyclic ring of the formula: ##STR9## as mentioned aboveand the side-chain having an electron-withdrawing group at the terminalnitrogen, and found that the compound (I') or (I) produced thus above ora salt thereof has, unexpectedly, excellent PDGF-inhibiting action (e.g.actions of inhibiting cell proliferation or vascular constriction),antihypertensive action, action of ameliorating nephropathy and,further, action of lowering cholesterol level. The present inventorshave further developed studies to accomplish the present invention.

More specifically, the present invention relates to

(1) a compound (I') or a salt thereof,

(2) a compound as described in (1) above, wherein Y is a hydrocarbongroup, a hydroxyl group or a mercapto group, each of which optionallyhas a substituent comprising at least one nitrogen atom,

(3) a compound as described in (1) above, wherein Y is a hydrocarbongroup, a hydroxyl group or a mercapto group, each of which optionallyhas a substituent comprising at least one electron-withdrawing group,

(4) a compound as defined in (1) above, wherein Y is a hydrocarbongroup, a hydroxyl group or a mercapto group, each of which optionallyhas a substituent comprising an amino group which is substituted with atleast one electron-withdrawing group,

(5) a compound as defined in (1) above, wherein Y is group of theformula: ##STR10## wherein B is an optionally substituted divalenthydrocarbon group;

X is a bond, an oxygen atom or a sulfur atom;

R² is a hydrogen atom or an optionally substituted hydrocarbon group, orR² and B may from a ring together with the adjacent nitrogen atom; and

R^(3a) is an electron-withdrawing group; or

R² and R^(3a) may form a ring together with the adjacent nitrogen atom,or a salt thereof,

(6) a compound (I) or a salt thereof,

(7) a compound as described in (1) above, wherein the nitrogenatom-containing heterocycleic ring is a 5- or 6-membered ring,

(8) a compound as described in (1) above, wherein the ring Q mayoptionally be substituted with 1 to 3 substituents selected from thegroup consisting of (i) halogen atom, (ii) a C₁₋₄ alkyl group, (iii) aC₁₋₄ alkoxy group, (iv) a C₁₋₄ alkylthio group, (v) a hydroxyl group,(vi) a carboxyl group, (vii) a cyano group, (viii) a nitro group, (ix) aamino group, (x) a mono- or di- C₁₋₄ alkyl amino group, (xi) a formylgroup, (xii) a mercapto group, (xiii) a C₁₋₄ alkyl-carbonyl group, (xiv)a C₁₋₄ alkoxy-carbonyl group, (xv) a sulfonyl group, (xvi) a C₁₋₄ alkylsulfonyl group, (xvii) a carbamoyl group and (xviii) a mono- or di- C₁₋₄alkyl-carbamoyl group,

(9) a compound as described in (1) above, wherein the ring Q isunsubstituted,

(10) a compound as described in (1) above, wherein R¹ is a hydrogenatom, an optionally substituted alkyl group, an optionally substitutedalkenyl group, an optionally substituted aralkyl group, an optionallysubstituted aryl group, an alkoxy carbonyl group, an alkyl carbamoylgroup or an alkanoyl group,

(11) a compound as described in (1) above, wherein R¹ is a hydrogenatom, a C₁₋₆ alkyl group or a phenyl group,

(12) a compound as described in (5) above, wherein R² is a hydrogenatom, an optionally substituted alkyl group or an optionally substitutedalkenyl group,

(13) a compound as described in (3) above, wherein theelectron-withdrawing group is (i) --SO₂ R⁴ (R⁴ is a n optionallysubstituted hydrocarbon group), (ii) --CO--R⁵ (R⁵ is a hydrogen atom oran optionally substituted hydrocarbon group), (iii) --COOR⁶ (R⁶ is anoptionally substituted hydrocarbon group) (iv) --CON(R⁷)R⁸ (wherein R⁷and R⁸ respectively are a hydrogen atom or an optionally substitutedhydrocarbon group, or, R⁷ and R⁸ form a ring together with the adjacentnitrogen atom), (v) a nitro group or (vi) a cyano group,

(14) a compound as described in (5) above, wherein B is a C₂₋₁₀ alkylenegroup,

(15) a compound as described in (5) above, wherein B is a group of theformula: ##STR11## wherein p and q respectively are independently aninteger of 0 to 5, (16) a compound as described in (5) above, wherein Bis a C₃₋₈ alkylene group,

(17) a compound as described in (6) above, which is one of the formula:##STR12## wherein X¹ is an oxygen atom or a sulfur atom, and the othersymbols are of the same meanings as defined in

(6) or a salt thereof,

(18) a compound as described in (6) above, which is the compound (II) or(VI) or a salt thereof,

(19) a compound as described in (17) above, wherein the ring Q isunsubstituted,

(20) a compound as described in (17) above, wherein R¹ is a hydrogenatom, an optionally substituted alkyl group or an optionally substitutedalkenyl group,

(21) a compound as described in (17) above, wherein R¹ is a hydrogenatom or a C₁₋₆ alkyl group,

(22) a compound as described in (17) above, wherein R² is a hydrogenatom or C₁₋₆ alkyl group,

(23) a compound as described in (17) above, wherein R2 is a hydrogenatom,

(24) a compound as described in (17) above, wherein X¹ is an oxygenatom,

(25) a compound as described in (17) above, wherein X¹ is a sulfur atom,

(26) a compound as described in (17) above, wherein B is a C₂₋₁₀alkylene group,

(27) a compound as described in (17) above, wherein B is a C₃₋₈ alkylenegroup,

(28) a compound as described in (17) above, wherein theelectron-withdrawing group represented by R³ is --SO₂ R^(4a) (R^(4a) isan optionally substituted alkyl group, an optionally substituted alkenylgroup, an optionally substituted aralkyl group or an optionallysubstituted aryl group),

(29) a compound as described in (28) above, wherein R^(4a) is ahalogeno-C₁₋₆ alkyl group,

(30) a compound as defined in (1) above represented by the formula:##STR13## wherein ring A^(a) is a nitrogen-containing heterocyclic ringwhich may have one oxo group, D is a bond or an optionally substituteddivalent hydrocarbon, ring W is an optionally substitutednitrogen-containing heterocyclic ring, ring Q may optionally besubstituted, and R³ is an electron-withdrawing group, or a salt thereof,

(31) a compound as defined in (30) above, wherein ring A^(a) is a 5- or6-membered nitrogen-containing heterocyclic ring which may have one oxogroup,

(32) a compound as defined in (30) above, wherein ##STR14## wherein Q isof the same meaning of (30) above, (33) a compound as defined in (30)above, wherein D is an optionally substituted divalent hydrocarbon,

(34) a compound as defined in (30) above, wherein ring W is anoptionally substituted 5- or 6-membered nitrogen-containing heterocyclicring,

(35) a compound as defined in (30) above, wherein R³ is --SO₂ R⁴ (R⁴ isan optionally substituted hydrocarbon group), --COR⁵ (R⁵ is a hydrogenatom or an optionally substituted hydrocarbon group), --COOR⁶ (R⁶ is anoptionally substituted hydrocarbon group) or --CON(R⁷)R⁸ (R⁷ and R⁸respectively are a hydrogen atom or an optionally substitutedhydrocarbon group, or R⁷ and R⁸ form a ring together with the adjacentnitrogen atom),

(36) a compound as defined in (30) above, wherein ring Q isunsubstituted,

(37) a compound as defined in (30) above, wherein ring W is ##STR15##(38) a compound as defined in (30) above, wherein D is C₁₋₆ alkylene,(39) a compound as defined in (1) above represented by the formula:##STR16## wherein j is 0 or 1, and the other symbols are of the samemeanings as defined in (30) above, or a salt thereof,

(40) a compound as defined in (39) above, wherein R³ is --SO₂ R⁴ (R⁴ isan optionally substituted hydrocarbon group), --COR⁵ (R⁵ is a hydrogenatom or an optionally substituted hydrocarbon group) or --COOR⁶ (R⁶ isan optionally substituted hydrocarbon group),

(41) a compound as defined (40) above, wherein R⁴, R⁵ and R⁶respectively are an optionally halogenated hydrocarbon group,

(42) a compound as defined in (39) above, wherein D is C₁₋₆ alkylene,

(43) a compound as defined in (39) above, wherein D is ethylene,

(44) a compound as defined in (39) above, wherein ring W is ##STR17##(45) a compound as defined in (39) above, wherein R³ is --SO₂ R⁴ (R⁴ isan optionally substituted hydrocarbon group),

(46) a compound as defined in (45) above, wherein R⁴ is an optionallyhalogenated C₁₋₆ alkyl group,

(47) a compound as defined in (39) above, wherein ring W is ##STR18##(48) a compound as defined in (39) above, wherein ring Q isunsubstituted, (49) a compound as defined in (39) above, wherein j is 0,

(50) a compound as defined in (1) above, which is1,2-dihydro-1-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one, or a salt thereof,

(51) a compound as defined in (1) above, which is 1,2-dihydro-1-2-(1-trifluoromethanesulfonylpiperidin-4-yl)ethane-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one, or a salt thereof,

(52) a compound as defined in (1) above, which is 1,2-dihydro-1-3-(trifluoromethanesulfonylpiperidin-4-yl)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one, or a salt thereof,

(53) a compound as defined in (1) above, which is4,5-dihydro-4-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one,or a salt thereof,

(54) a compound as defined in (1) above, which is 4,5-dihydro-4-2-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one,or a salt thereof,

(55) a compound as described in (1), which is 4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-oneor a salt thereof, or 1,2-dihydro-3-methyl-1-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacylcopentcd!inden-2-one or a salt thereof,

(56) a process for producing the compound as described in (1) above,which comprises reacting a compound of the formula: ##STR19## whereinthe symbols are defined in (1) above, or a salt thereof, with a compoundof the formula:

    E.sup.1 --Y

wherein E¹ is a leaving group and the other symbol is defined in (1)above, or a salt thereof,

(57) a compound of the formula: ##STR20## wherein R^(1a) is a halogenatom, an optionally substituted hydrocarbon group or an acyl group,except for methyl group as R^(1a) ;

R^(1b) is a halogen atom, an optionally substituted hydrocarbon group oran acyl group; and the other symbols are of the same meanings as defindabove, or a salt thereof,

(58) a composition which comprises the compound as described in (1)above,

(59) a pharmaceutical composition which comprises the compound asdescribed in (1) above,

(60) a pharmaceutical composition for suppressing platelet-derivedgrowth factor, which comprises the compound as described in (1) above,

(61) a therapeutic composition for hypertension, which comprises thecompound as described in (1) above,

(62) a therapeutic composition for renal diseases, which comprises thecompound as described in (1) above, and

(63) a composition for lowering lipid level, which comprises thecompound as described in (1) above.

The term "nitrogen-containing heterocyclic ring" used in the presentspecification means, for example, 5- to 10-membered ring containing, twonitrogen atoms as hetero-atoms. Among them, 5- or 6-membered ring iswidely used. These ring may be saturated or unsaturated, and may contain1 or 2 hetero atoms (e.g. sulfur atom, oxygen atom, nitrogen atom). Morespecifically, for example, the following ones ##STR21## are employed.These "nitrogen-containing heterocyclic rings" may optionally besubstituted with one or two of oxo or thioxo groups.

The term "divalent hydrocarbon group" used in the present specificationmeans, for example, divalent chain-like hydrocarbon groups includingC₁₋₁₅ alkylene groups (e.g. methylene, ethylene, propylene, butylene,pentamethylene, hexamethylene, heptamethylene and octamethylene), C₂₋₁₆alkenylene groups (e.g. vinylene, propenylene, 1-butenylene,2-butenylene, 1-pentenylene, 2-pentenylene and 3-pentenylene), C₂₋₁₆alkynylene groups (e.g. ethynylene, propynylene, 1-butynylene,2-butynylene, 1-pentynylene, 2-pentynylene and 3-pentynylene), phenylenegroup or a combination of them.

As substituents which the said "divalent hydrocarbon group" optionallyhas, mention is made of, for example, optionally substituted alkylgroups, optionally substituted aralkyl groups and optionally substitutedaryl groups, and optionally substituted alkyl groups are preferable. Thesaid "phenylene group" may be substituted.

As substituents which the said "phenylene group" optionally has, mentionis made of one to four selected from, for example, halogen atoms (e.g.fluorine, chlorine, bromine and iodine), C₁₋₄ alkyl groups (e.g. methyl,ethyl, propyl, isopropyl and butyl), C₁₋₄ alkoxy groups (e.g. methoxy,ethoxy, propoxy and isopropoxy), C₁₋₄ alkylthio groups (e.g. methylthio,ethylthio, propylthio and isopropylthio), hydroxyl group, carboxylgroup, cyano group, nitro group, amino group, mono- or di- C₁₋₄ aminogroups (e.g. methylamino, ethylamino, dimethylamino and diethylamino),formyl group, mercapto group, C₁₋₄ alkyl-carbonyl groups (e.g. acetyl,propionyl and butyryl), C₁₋₄ alkoxy-carbonyl groups (e.g.methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl), sulfonyl group,C₁₋₄ alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl andpropylsulfonyl), carbamoyl group and mono- or di- C₁₋₄ alkyl-carbamoylgroups (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyland N,N-diethylcarbamoyl).

The term "halogen atom" used in the present specification means, forexample, fluorine, chlorine, bromine and iodine.

The "hydrocarbon group" of the term "optionally substituted hydrocarbongroup" used in the present specification means, for example, alkylgroup, cycloalkyl group, alkenyl group, aralkyl group and aryl group.

Examples of the substituents, which the said "hydrocarbon group"optionally has, use is made of the substituents which the said "alkylgroup", "cycloalkyl group", "alkenyl group", "aralkyl group" and "arylgroup" optionally have.

As said "alkyl group", use is made of, for example, "straight-chain orbranched C₁₋₁₅ alkyl group" such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, tridecyl, tetradecyl and pentadecyl.

As said "cycloalkyl group", use is made of, for example, "C₃₋₈cycloalkyl group" such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

Examples of the substituents, which the said "alkyl group" and"cycloalkyl group" optionally have, include (i) nitro group, (ii)hydroxyl group, (iii) cyano group, (iv) carbamoyl group, (v) mono- ordi- C₁₋₄ alkyl-carbamoyl groups (e.g. N-methylcarbamoyl,N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl), (vi)carboxyl group, (vii) C₁₋₄ alkoxy-carbonyl groups (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl), (viii) sulfonylgroup, (ix) halogen atoms (e.g. fluorine, chlorine, bromine and iodine),(x) C₁₋₄ alkoxyl groups (e.g. methoxy, ethoxy, propoxy and isopropoxy),(xi) phenoxy group, (xii) halogenophenoxy groups (e.g. o-, m- orp-chlorophenoxy, and o-, m- or p-bromophenoxy), (xiii) C₁₋₄ alkylthiogroups (e.g. methylthio, ethylthio, n-propylthio, isopropylthio andn-butylthio), (xiv) mercapto group, (xv) phenylthio group, (xvi)pyridylthio group, (xvii) C₁₋₄ alkylsulfinyl groups (e.g. methylsulfinyland ethylsulfinyl), (xviii) C₁₋₄ alkylsulfonyl groups (e.g.methylsulfonyl and ethylsulfonyl), (xix) amino group, (xx) C₁₋₃acylamino groups (e.g. acetylamino and propionylamino), (xxi) mono- ordi- C₁₋₄ alkylamino groups (e.g. methylamino, ethylamino, dimethylaminoand diethylamino), (xxii) 4- to 6- membered cyclic amino groups (e.g.1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino and1-piperazinyl), (xxiii) C₁₋₃ acyl groups (e.g. formyl and acetyl),(xxiv) benzoyl group and (xxv) 5 to 10 membered heterocyclic groups(e.g. 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2, 4- or 5-oxazolyl, 1,2,3- or1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl and isoquinolylindolyl). Thesaid "alkyl group" and "cycloalkyl group" optionally have 1 to 5 ofthese substituents at any substituable positions.

Preferable examples of the said "alkyl group" include C₁₋₆straight-chain or branched alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. Asthe substituents which the said "C₁₋₆ alkyl groups" optionally have, useis made of 1 to 3 of, for example, halogen atoms, C₁₋₄ alkoxyl group,hydroxyl group, C₁₋₄ alkoxy-carbonyl groups, carboxyl group, carbamoyylgroup, mono- or di- C₁₋₄ alkylcarbamoyl groups and pyridylthio group.

Examples of the said "alkenyl group" include "C₂₋₁₈ alkenyl groups" suchas vinyl, allyl, isopropenyl, 3-butenyl, 3-octenyl and 9-octadecenyl. Asthe substituents which the said "alkenyl groups" optionally have, use ismade of, for example, the same ones as those which the above-mentioned"alkyl group" optionally has.

Preferable examples of the said "alkenyl group" include C₂₋₆ alkenylgroups such as vinyl, allyl, 2-butenyl and 3-butenyl. As thesubstituents which the said "C₂₋₆ alkenyl groups" optionally has, use ismade of, for example, the same ones as those which the above-mentioned"C₁₋₆ alkyl group" optionally has.

As the said "aralkyl group", use is made of, for example, C₇₋₁₆ aralkylgroups, which are specifically exemplified by phenyl- C₁₋₆ alkyl groupssuch as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl, andnaphthyl- C₁₋₆ alkyl group such as (1-naphthyl)methyl,2-(1-naphthyl)ethyl and 2-(2-naphthyl)ethyl.

Examples of the substituents, which the said "aralkyl group" optionallyhas, include halogen atoms (e.g. fluorine, chlorine, bromine andiodine), C₁₋₄ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl andbutyl), halogeno-C₁₋₄ alkyl groups (e.g. trifluoromethyl,trichloromethyl), C₂₋₆ alkenyl groups (e.g. vinyl, allyl, 2-butenyl and3-butenyl), C₁₋₃ acyl groups (e.g. formyl and acetyl), C₁₋₄ alkoxylgroups (e.g. methoxy, ethoxy, propoxy and isopropoxy), nitro group,cyano group, hydroxyl group, C₁₋₄ alkoxy-carbonyl groups (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andisopropoxycarbonyl), carbamoyl group, mono- or di- C₁₋₄ alkyl-carbamoylgroups (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyland N,N-diethylcarbamoyl) and mono- or di- C₂₋₄ alkenyl-carbamoyl groups(e.g. N-vinylcarbamoyl). The said "aralkyl group" may optionally have 1to 4 of these substituents at any substituable position.

As the said "aryl group", use is made of, for example, aromaticmonocyclic, dicyclic or tricyclic C₆₋₁₄ aryl groups exemplified byphenyl, 1-naphthyl, 2-naphthyl, phenanthryl and anthryl.

As the substituents which the said "aryl group" optionally has, use ismade of, besides the substituents which the said "aralkyl group" mayoptionally have, oxo group. The said "aryl group" may optionally have 1to 4, preferably 1 or 2, of these substituents at any substitutablepositions. Examples of the aryl group having oxo group includebenzoquinonyl, naphthoquinolyl and anthraquinonyl.

The term "electron-withdrawing group" used in the present specificationis exemplified by (i) --SO₂ R⁴, (ii) --CO--R⁵, (iii) --COOR⁶,(iv)--CON(R⁷)R⁸, (v) a nitro group and (vi) a cyano group, preferably --SO₂R⁴, --CO--R⁵ and --COOR⁶, especially --SO₂ R⁴ is commonly used. R⁴stands for an optionally substituted hydrocarbon group; R⁵ stands for ahydrogen atom or an optionally substituted hydrocarbon group; R⁶ standsfor an optionally substituted hydrocarbon group; R⁷ and R⁸ independentlystand for a hydrogen atom or an optionally substituted hydrocarbongroup, or R⁷ and R⁸ form, combined with the adjacent nitrogen atom, annitrogen atom-containing heterocyclic ring.

The term "acyl group" used in the present specification is exemplifiedby the acyl group derived from carboxylic acid, which is exemplified byalkoxycarbonyl group, alkylcarbamoyl group and alkanoyl group. As thesaid "alkoxycarbonyl group", use is made of C₁₋₆ alkoxycarbonyl groupsincluding, for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl and tert-pentyloxycarbonyl.

As the said "alkylcarbamoyl group", use is made of mono-C₁₋₆-N-alkylcarbamoyl groups, for example, NNmethylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl and N-butylcarbamoyl, and di-C₁₋₆-N,N-dialkylcarbamoyl groups, for example, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl andN-ethyl-methylcarbamoyl, and 4- to 6-membered cyclic carbamoyl groupsformed by combination of the dialkyl portions with each other (e.g.1-azetidinylcarbonyl, morpholinocarbonyl, 1-pyrrolidinylcarbonyl,1-piperidinocarbonyl and 1-piperazinylcarbonyl).

As the said "alkanoyl group", use is made of formyl, C₁₋₆ alkyl-carbonylgroup (e.g. acetyl, propionyl).

In the above-mentioned formula, the ring A stands for anitrogen-containing heterocyclic ring having two nitrogen atomscontaining the nitrogen atom at the head of the bridge in the condensedring, which be further substituted with oxo or thioxo.

Preferable examples of the ring A include 5- or 6-memberednitrogen-containing heterocyclic ring optionally substituted with one ortwo oxo groups. Especially, the following ones are commonly employed.##STR22##

In the above-mentioned formula, the ring Q is optionally substituted.

Examples of the substituents, which the ring Q optionally has, includehalogen atoms (e.g. fluorine, chlorine, bromine and iodine), C₁₋₄ alkylgroups (e.g. methyl, ethyl, propyl, isopropyl and butyl), halogeno-C₁₋₄alkyl groups (e.g. trifluoromethyl, trichloromethyl), C₁₋₄ alkoxy groups(e.g. methoxy, ethoxy, propoxy and isopropoxy), halogeno-C₁₋₄ alkoxygroups (e.g. trifluoromethoxy, trichloromethoxy), CI₄ alkylthio groups(e.g. methylthio, ethylthio, propylthio and isopropylthio),halogeno-C₁₋₄ alkylthio groups (e.g. trifluoromethylthio,trichloromethylthio), hydroxyl group, carboxyl group, cyano group, nitrogroup, amino group, mono- or di- C₁₋₄ alkyl amino groups (e.g.methylamino, ethylamino, dimethylamino and diethylamino), formyl group,mercapto group, C₁₋₄ alkyl-carbonyl groups (e.g. acetyl, propionyl andbutyryl), C₁₋₄ alkoxy-carbonyl groups (e.g. methoxycarbonyl,ethoxycarbonyl and propoxycarbonyl), sulfo group, C₁₋₄ alkylsulfonylgroups (e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl),carbamoyl group and mono- or di- C₁₋₄ alkyl-carbamoyl groups (e.g.N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl andN,N-diethylcarbamoyl). The ring Q may be substituted with one to threeof these substituents on any substitutable position. The ring Q ispreferably unsubstituted.

In the above-mentioned formulae, R stands for a hydrogen atom, a halogenatom, an optionally substituted hydrocarbon group or acyl group.

Preferable examples of R¹ include a hydrogen atom, optionallysubstituted alkyl groups, optionally substituted alkenyl groups,optionally substituted aralkyl groups, optionally substituted arylgroups, alkoxycarbonyl groups, alkylcarbamoyl groups and alkanoylgroups; especially a hydrogen atom, C₁₋₆ alkyl groups (e.g. methyl,ethyl, propyl, isopropyl and butyl) or phenyl group are preferably used,and, a hydrogen atom is employed most preferably.

In the above-mentioned formula, Y stands for an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group or anoptionally substituted mercapto group, excluding methyl group as Y.

Examples of the optionally substituted hydrocarbon group shown by Yinclude those described in respect of the above-mentioned "optionallysubstituted hydrocarbon group", excluding unsubstituted methyl group.

Examples of the substituents, which the hydroxyl group or the mercaptogroup shown by Y optionally has, include optionally substitutedhydrocarbon group, the groups containing at least one nitrogen atomand/or the groups containing at least one electron-withdrawing groups.

Preferable examples of the substituents, which the hydroxyl group or themercapto group shown by Y optionally has, include optionally substitutedhydrocarbon group. As the said "optionally substituted hydrocarbongroup", use is made of the same ones as the above-mentioned "optionallysubstituted hydrocarbon group".

Preferable examples of the substituents, which the hydrocarbon group,the hydroxyl group and the mercapto group shown by Y optionally has,include the groups containing at least one nitrogen atom and/or thegroups containing at least one electron-withdrawing group, especiallythe groups containing an amino group substituted with at least oneelectron-withdrawing group.

As "the group containing at least one nitrogen atom" mentioned above,use is made of, for example, alkylaminoalkyl groups aralkylaminoalkylgroups, arylaminoalkyl groups, alkylaminoaralkyl groups,aralkylaminoaralkyl groups, arylaminoaralkyl groups, alkylaminoarylgroups, aralkylaminoaryl groups, arylaminoaryl groups, aminoalkylgroups, aminoaralkyl group and aminoaryl groups.

As "the group containing at least one electron-withdrawing group", useis made of, for example, the hydrocarbon groups containing at least one"electron-withdrawing group as mentioned above".

As "the group containing an amino group which is substituted with atleast one electron-withdrawing group", use is made of, for example, thehydrocarbon groups containing an amino group substituted with at leastone "electron-withdrawing group as mentioned above".

The most preferable examples of Y include the groups represented by theformula ##STR23## wherein the symbols are of the same meaning as definedabove.

In the above-mentioned formula, B stands for an optionally substituteddivalent hydrocarbon group. Specific examples of the group include thoserepresented by (i) ##STR24## wherein m, n and o independently areintegers of 0 to 5, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently standfor a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aralkyl group or an optionally substituted arylgroup, and, R⁹ and R¹⁰ ; R¹¹ and R¹² ;, R¹³ and R¹⁴ ; R⁹ or R¹⁰ and R² ;R¹¹ or R¹² and R² ;, or, R¹³ or R¹⁴ and R² may respectively be combinedto form rings, and R⁹ or R¹¹ may be combined with R¹³ or R¹⁴respectively to form rings, or (ii) ##STR25## wherein phenylene groupmay be substituted, and, p and q are independently an integer of 0 to 5.Examples of the optionally substituted alkyl, aralkyl or aryl groupshown by R⁹ to R¹⁴ include those described in respect of theabove-mentioned "optionally substituted hydrocarbon groups". The ringsformed by combination of R⁹ and R¹⁰, R¹¹ and R¹², and R¹³ and R¹⁴ areexemplified by C₃₋₈ cycloalkanes including cyclopropane, cyclobutane,cyclopentane and cyclohexane. The rings formed by combination of R⁹ orR¹⁰ and R² ; R¹¹ or R¹² and R² ; or R¹³ or R¹⁴ and R² are exemplified byazetidine, pyrrolidine or piperidine. The rings formed by combination ofR⁹ or R¹¹ with R¹³ or R¹⁴, respectively are exemplified by C₃₋₈cycloalkanes including cyclopropane, cyclobutane, cyclopentane andcyclohexane.

Preferable examples of R⁹ to R¹⁴ include a hydrogen atom or C₁₋₄ alkylgroups (e.g. methyl, ethyl, propyl and isopropyl), and, especially, ahydrogen atom or methyl group is preferably used.

Preferable examples of B include C₂₋₁₀ alkylene groups (e.g. ethylene,propylene, butylene, pentamethylene, hexamethylene, heptamethylene andoctamethylene), and, among them, especially C₃₋₈ alkylene groups (e.g.ethylene, propylene, butylene, pentamethylene, hexamethylene andheptamethylene) are commonly employed. In the above-mentioned formulae,X stands for a bond, an oxygen atom or a sulfur atom. Preferable exampleof X is a bond.

In the above-mentioned formulae, R² stands for a hydrogen atom or anoptionally substituted hydrocarbon group, and, R² and B may optionallyform a ring together with the adjacent nitrogen atom.

Preferable examples of R² include a hydrogen atom, optionallysubstituted alkyl groups or optionally substituted alkenyl groups,especially a hydrogen atom is commonly used.

In the above-mentioned formulae, R³ and R^(3a) stand for anelectron-withdrawing group, or R², R³ and R^(3a) may form a ringtogether with the adjacent nitrogen atom. Examples of theelectron-withdrawing group include (i) --SO₂ R⁴ (R⁴ stands for anoptionally substituted hydrocarbon group), (ii) --CO--R⁵ (R⁵ stands fora hydrogen atom or an optionally substituted hydrocarbon group), (iii)--COOR⁶ (R⁶ stands for an optionally substituted hydrocarbon group),(iv) --CON(R⁷)R⁸ (R⁷ and R⁸ each stand for a hydrogen atom or anoptionally substituted hydrocarbon group, or R⁷ and R⁸ may form a ringtogether with the adjacent nitrogen atom), (v) a nitro group and (vi) acyano group.

Examples of the electron-withdrawing group include --SO₂ R^(4a),--CO--R^(5a) and --COOR^(6a) (R^(4a), R^(5a) and R^(6a) each stand foran optionally substituted alkyl group, an optionally substituted alkenylgroup, an optionally substituted aralkyl group or an optionallysubstituted aryl group), especially --SO₂ R^(4a) (R^(4a) stands for anoptionally substituted alkyl group, an optionally substituted alkenylgroup, an optionally substituted aralkyl group or an optionallysubstituted aryl group) is commonly used among others.

Preferable examples of R⁴ include an optionally substituted alkyl group,especially a halogeno- C₁₋₆ alkyl group (e.g. chloromethyl,trifluoromethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl).

Preferable examples of R⁵ include an optionally substituted alkyl group,especially a halogeno- C₁₋₆ alkyl group (e.g. chloromethyl,trifluoromethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl).

Preferable examples of R⁶ include an optionally substituted alkyl group,especially a halogeno- C₁₋₆ alkyl group (e.g. chloromethyl,trifluoromethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl).

Preferable examples of R and R include a hydrogen atom or an optionallysubstituted alkyl group, especially a hydrogen atom or a halogeno- C₁₋₆alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyland 3,3,3-trifluoropropyl).

Examples of the ring, which R², R³ and R^(3a) form together with theadjacent nitrogen atom, include pyrrolidin-2-one, piperidin-2-one,indolin-2-one, isoindolin-1-one, isoindoline-1,3-dione,oxazolidin-2-one, oxazolidine-2,4-dione, thiazolidin-2-one,thiazolidine-2,4-dione and 1,2-benzisothiazol-3(2H)-one. These ringsoptionally have substituents such as electron-withdrawing groups. As thesaid "electron-withdrawing group", use is made of, for example, theabove-mentioned "electron-withdrawing groups".

Preferable examples of the compounds (I') are shown as follows:

Compounds of the following formula or salts thereof. ##STR26## whereinX¹ stands for an oxygen atom or a sulfur atom, and the other symbols areof the same meaning as defined above, especially the compound (II) or(VI). In these compounds (II) to (VII"),

(1) a compound, wherein ring Q is unsubstituted, is preferable;

(2) a compound, wherein R¹ stands for a hydrogen atom, an optionallysubstituted alkyl group or an optionally substituted alkenyl group, ispreferable, and, especially those, wherein R¹ stands for a hydrogen atomor a C₁₋₆ alkyl group (e.g. methyl, ethyl, propyl, isopropyl and butyl),are preferably used;

(3) a compound, wherein R² stands for a hydrogen atom or a C₁₋₆ alkylgroup (e.g. methyl, ethyl, propyl, isopropyl and butyl), is preferable,and, especially those, wherein R² stands for a hydrogen atom, arepreferably used;

(4) a compound, wherein X¹ stands for an oxygen atom, is preferable; (5)a compound, wherein X¹ stands for a sulfur atom, is preferable;

(6) a compound, wherein B stands for a C₂₋₁₀ alkylene group (e.g.ethylene, propylene, butylene, pentamethylene, hexamethylene andoctamethylene), is preferable, and, especially those, wherein B standsfor a C₃₋₈ alkylene group (e.g. propylene, butylene, pentamethylene,hexamethylene and heptamethylene), are preferable;

(7) a compound, wherein the electron-withdrawing group shown by R³ is--SO₂ R^(4a) (R^(4a) stands for an optionally substituted alkyl group,an optionally substituted alkenyl group, an optionally substitutedaralkyl group or an optionally substituted aryl group), is preferable;and

(8) a compound, wherein R⁴ stands for a halogeno- C₁₋₆ alkyl group (e.g.chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and3,3,3-trifluoropropyl), is preferable.

More preferable example of the compound (I) is a compound represented bythe formula: ##STR27## wherein the all symbols are of the same meaningsas defined above.

In the compound (A), ring Q is of the same meaning as defined above, andpreferably unsubstituted ring.

In the compound (A), ring A^(a) is a nitrogen-containing heterocyclicring which may have one oxo group. The "nitrogen-containing heterocyclicring" have two nitrogen atoms other than carbon atoms. Preferableexamples of the nitrogen-containing heterocyclic ring represented byA^(a) are a 5- to 10-membered nitrogen-containing heterocyclic ring, andmore preferably 5- or 6-membered nitrogen-containing heterocyclic ring.

In the compound (A), examples of the moiety: ##STR28## wherein ring Q isof the same meaning as defined above, and preferably the moiety:##STR29## wherein j is 0 or 1, and preferably 0, and ring Q is of thesame meaning as defined above.

In the compound (A), D is a bond or an optionally substituted divalenthydrocarbon. D is preferably an optionally substituted divalenthydrocarbon. The "optionally substituted divalent hydrocarbon" is of thesame meaning as defined in above. The "divalent hydrocarbon" ispreferably, for example, C₁₋₁₅ alkylene group (e.g. methylene, ethylene,propylene, butylene, pentamethylene, hexamethylene, heptamethylene,octamethylene), C₂₋₁₆ alkenylene group (e.g. vinylene, propenylene,1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene,3-pentenylene), C₂₋₁₆ alkynylene group (e.g. ethynylene, propynylene,1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene,3-pentynylene), phenylene group, and a combination of them. And morepreferable example of the "divalent hydrocarbon group" is C₁₋₁₅ alkylenegroup (e.g. methylene, ethylene, propylene, butylene, pentamethylene,hexamethylene, heptamethylene, octamethylene).

The substituent of the "divalent hydrocarbon group" is exemplified bythe same substituents as those of the "divalent hydrocarbon group" asmentioned above.

In the compound (A), ring W is an optionally substitutednitrogen-containing heterocyclic ring, and preferably an optionallysubstituted 5- or 6-membered nitrogen-containing heterocyclic ring.

Preferable examples of the "nitrogen-containing heterocyclic ring" arethe moiety: ##STR30## and more preferably the moiety: ##STR31## and mostpreferably the moiety: ##STR32##

The substituent of the "nitrogen-containing heterocyclic group" isexemplified by the same one as the substituent of ring Q.

Preferable example of the compound (A) is a compound represented by theformula: ##STR33## wherein all symbols are of the same meanings asdefined above.

In the compound (A-a), ring Q is preferably unsubstituted pyridine ring.

In the compound (A-a), R³ is preferably --SO₂ R⁴ (R⁴ is an optionallysubstituted hydrocarbon group), --COR⁵ (R⁵ is a hydrogen atom is anoptionally substituted hydrocarbon group) or --COOR⁶ (R6 is anoptionally substituted hydrocarbon group). And, preferable examples ofR⁴, R⁵ and R⁶ are an optionally halogenated hydrocarbon group (e.g. C₁₋₆alkyl group which may have 1 to 5 halogen atoms such as methyl, ethyl,propyl, isopropyl, butyl, chloromethyl, trifluoromethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, or pentafluoroethyl).

In the compound (A-a), D is preferably a C₁₋₆ alkylene (e.g. methylene,ethylene, propylene, butylene, pentamethylene), and more preferablyethylene.

In the compound (A-a), ring W is preferably a moiety: ##STR34## and morepreferably a moiety: ##STR35##

In the compound (A-a), j is preferably 0.

In the compound (A-a), R³ is more preferably --SO₂ R⁴ (R⁴ is anoptionally substituted hydrocarbon group). And, R⁴ is preferably a C₁₋₆alkyl group which may have 1 to 5 halogen atoms such as methyl, ethyl,propyl, isopropyl, butyl, chloromethyl, trifluoromethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, or pentafluoroethyl).

As preferable salts of the compound (I') (hereinafter referred to as"compound (I')" including the compound (I)), mention is especially madeof pharmaceutically acceptable salts and physiologically acceptable acidaddition salts. These salts are exemplified by those with inorganicacids (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid andsulfuric acid) or with organic acids (e.g. acetic acid, formic acid,propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid,citric acid, malic acid, oxalic acid, benzoic acid, methansulfonic acidand benzenesulfonic acid). Further, when the compound (I') of thepresent invention has an acid group such as carboxylic group, it mayoptionally form a salt with, for example, an inorganic base (e.g. analkali metal or an alkaline earth metal such as sodium, potassium,calcium and magnesium, or ammonia) or an organic base (e.g. a tri- C₁₋₃alkylamine such as triethylamine).

As the starting compounds for producing the desired compound (I') of thepresent invention, similar salts to those mentioned above are employed,and they are not specifically limited unless they exert undesirableinfluence upon the reaction.

The compound (I') or a salt thereof has, in some instances, asymmetriccarbons in the molecule. When two kinds of stereoisomers ofR-configuration and S-configurated isomers, are present, each of themand a mixture of them are all included in the scope of the presentinvention.

Preferable practical examples of the compound (I') and salts thereof areset forth as follows:

1,2-dihydro-3-methyl-1- 4-(trifluoromethanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one,

1,2-dihydro-3-methyl-1- 5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one,

1,2-dihydro-3-methyl-1-3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one,

1,2-dihydro-3-methyl-1- 4-(2,2,2-trifluoro)ethanesulfonamido!butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one,

3-methyl-2-4-(trifluoromethanesulfonamido)butan-1-ylthio!-1,4,7b-triazacyclopentcd!inden,

4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene,

4,5-dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene,

4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione,

4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one,

4,5-dihydro-5-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one,

4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-5-one,

1,2-dihydro-1-(1-trifluoromethanesulfonylpiperidine-4-ylmethyl)-1,4,7b-triazacyclopentocd!inden-2-one,

1,2-dihydro-1-2-(1-trifluoromethanesulfonylpiperidin-4-yl)ethane-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one,

1,2-dihydro-1-3-(1-trifluoromethanesulfonylpiperidin-4-yl)propane-1-yl!-1,4,7b-triazacyclopentcd!indene-2-one,

4,5-dihydro-4-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one,

4,5-dihydro-4-2-(1-trifluoromethanesulfonylpiperidine-4-yl)ethane-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one,and their salts (preferable example of the salts is hydrochloride).Especially preferable practical examples of the compound (I') and saltsthereof are set forth as follows;

1,2-dihydro-3-methyl-1-5-(trifluoromethanesulfonamido)pentan-1-yl!-1-4,7b-triazacyclopentcd!inden-2-one,

4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one,

1,2-dihydro-1-2-(1-trifluoromethanesulfonylpiperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one and their salts (preferable example of the salts ishydrochloride).

The compound (I') or a salt thereof of the present invention can besynthesized by the following method. ##STR36## wherein E¹ stands for aleaving group such as halogen (e.g. chlorine, bromine, iodine),methanesulfonyloxy and p-toluenesulfonyloxy; the other symbols are ofthe same meaning as defined above.

The compound (XII) include novel compounds represented by the formula##STR37## wherein R^(1a) stands for a halogen atom, an optionallysubstituted hydrocarbon group or an acyl group, except for methyl groupas R^(1a) ;

R^(1b) stands for a halogen atom, an optionally substituted hydrocarbongroup or an acyl group; and the other symbols are of the same meaning asdefined above, or a salt thereof.

Practically the compound (I') or a salt thereof of the present inventioncan be synthesized by, for example, a process for producing the compound(I') or a salt thereof which comprises reacting a compound of theformula ##STR38## wherein the symbols are of the same meanings asdefined above, or a salt thereof, with a compound of the formula

    E.sup.1 --Y

wherein the symbols are of the same meanings as defined above, or a saltthereof. Hereinafter, in the formula containing the symbols "B" and "R²", the symbols "B" and "R² " include the definition "R² and B may form aring together with the adjacent nitrogen atom", without a broken linebetween "B" and "R² " being indicated. More, specifically, the compound(I) or a salt thereof of the present invention can be synthesized by,for example, the following methods. ##STR39## wherein G¹ stands for ahalogen (e.g. chloro, bromo or iodo) or --OR³ ; E¹ stands for a leavinggroup such as halogen (e.g. chlorine, bromine or iodine),methanesulfonyloxy and p-toluenesulfonyloxy; and the other symbols areof the same meanings as defined above.

And, by subjecting such compounds as shown below to ring-closurereaction (e.g. Mannich reaction or dehydrative ring-closure), thecompound (I) or a salt thereof can also be synthesized. ##STR40##wherein j denotes 0 or 1, J stands for a hydrogen atom or a protectinggroup (e.g. benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl,trityl and benzyl), R¹⁵ stands for an optionally substituted alkylgroup, and the other symbols are of the same meanings as defined above.

In more detail, for example, the synthesis can be carried out by thefollowing methods.

(1) A method of producing the compound (I) or a salt thereof by allowinga compound represented by the general formula ##STR41## wherein thesymbols are of the same meanings as defined above or a salt thereof toreact with a compound represented by the general formula G¹ --SO₂ --R⁴(G¹ stands for a halogen such as chlorine, bromine and iodine, or R4SO₂--O--, and R⁴ is of the same meaning as defined above) or a saltthereof.

(2) A method of producing the compound (I) or a salt thereof by allowinga compound represented by the general formula ##STR42## wherein thesymbols are of the same meanings as defined above or a salt thereof toreact with a compound represented by the general formula ##STR43##wherein E¹ stands for a leaving group such as a halogen (e.g. chlorine,bromine and iodine), methanesulfonyloxy and p-toluenesulfonyloxy, andthe other symbols are of the same meaning as defined above, or a saltthereof.

(3) A method of producing the compound (II), (VI) or salts of them,which comprises subjecting a compound represented by the general formula##STR44## wherein j denotes 0 or 1, J stands for a hydrogen atom or aprotecting group (e.g. benzyloxycarbonyl, tert-butoxycarbonyl,trifluoroacetyl, trityl and benzyl), and the other symbols are of thesame meanings as defined above or a salt thereof totrichloroacetylation, then, upon necessity, deprotection of theprotecting group J, and, further subjecting the resultant compound toring-closure reaction.

(4) A method of producing the compound (IV) or a salt thereof bysubjecting a compound represented by the general formula ##STR45##wherein the symbols are of the same meanings as defined above or a saltthereof to Mannich reaction to cause ring closure.

(5) A method of producing the compound (V) or a salt thereof by allowinga compound represented by the general formula ##STR46## wherein R¹⁵stands for a C₁₋₄ alkyl group, and the other symbols are of the samemeanings as defined above or a salt thereof to react with a compoundrepresented by the general formula ##STR47## wherein the symbols are ofthe same meanings as defined above or a salt thereof.

These methods of producing the target compounds and those of producingthe starting compounds are described as follows in further detail.

(A) method: In the case where R³ of the compound (I) is --SO₂ R⁴,##STR48## wherein G¹ stands for a halogen (e.g. chlorine) or R⁴ SO₂--O--, and the other symbols are of the same meanings as defined above.

(B) method: In the case where R³ of the compound (I) is --CO--R⁵,##STR49## wherein G² stands for a halogen (e.g. chlorine) or R⁵ CO--O--,and the other symbols are of the same meanings as defined above.

(C) method: In the case where R³ of the compound (I) is --COOR⁶,##STR50## wherein G³ stands for a halogen (e.g. chlorine) or R⁶ CO₂--O--, and the other symbols are of the same meanings as defined above.

(D) method: In the case where R³ of the compound (I) is --CON(R⁷)R⁸,##STR51## wherein G⁴ stands for a phenoxy or halogen (e.g. chlorine),and the other symbols are of the same meanings as defined above.

(E) method: ##STR52## wherein E¹ stands for a halogen (e.g. chlorine,bromine and iodine) or a leaving group such as methanesulfonyloxy andp-toluenesulfonyloxy, and the other symbols are of the same meanings asdefined above.

(F) method: ##STR53## wherein the symbols are of the same meanings asdefined above. (G) method: ##STR54## wherein the symbols are of the samemeanings as defined above. (H) method: ##STR55## wherein j denotes 0 or-1, J stands for a hydrogen atom or a protective group of secondaryamino group (e.g. benzyloxycarbonyl, tert-butoxycarbonyl,trifluoroacetyl, trityl and benzyl), and the other symbols are of thesame meanings as defined above.

(I) method: ##STR56## wherein the symbols are of the same meanings asdefined above. (J) method: ##STR57## wherein R¹⁵ stands for an alkylgroup, and the other symbols are of the same meanings as defined above.

(K) method: In the case where X¹ of the compound (II) is a sulfur atom,##STR58## wherein X¹ stands for a sulfur atom, and the other symbols areof the same meanings as defined above.

(L) method: In the case where R² of the compound (I) is a hydrogen atom,##STR59## wherein J¹ stands for a protecting group of an amino group,and the other symbols are of the same meanings as defined above.

In the above-mentioned methods A to L, a compound, which can form asalt, may be used in the form of salt. Examples of such a salt includethose as described in the above-mentioned compound (I'). In thefollowing description of the respective methods, of a salt of eachcompound may also be included.

In the reaction between the compound (XII) and the compound E¹ --Y inthe method of producing the compound (I'), one equivalent to a largeexcess amount (1 to 10 equivalents) of the compound E¹ --Y is employedrelative to the compound (XII). In this case, a basic compound such assodium hydroxide, potassium hydroxide, potassium hydroxide,triethylamine, diisopropylethylamine and 1,8-diazabicyclo5,4,0!-7-undecene may be used in an amount of 1 to 10 equivalents. Thereaction temperature ranges from --20 to 200° C. Examples of thesolvents to be employed include water, lower alcohols (e.g. methanol,ethanol and propanol), ketones (e.g. acetone and methyl ethyl ketone),ethers (e.g. tetrahydrofuran) and aprotic polar solvents (e.g.N,N-dimethylformamide and dimethylsulfoxide). For the said reaction, asa reaction promotor, sodium iodide may be added in an amount rangingfrom 1 equivalent to a large excess (1 to 10 equivalents). The reactiontime ranges usually from 10 minutes to 24 hours, preferably from 0.5 to6 hours.

In the reaction between the compound (VIII) and the compound G¹ --SO₂--R⁴ in the method A, one equivalent to a large excess amount (1 to 10equivalents) of the compound G¹ --SO₂ --R⁴ is employed relative to thecompound (VIII). In this case, an inorganic base such as potassiumcarbonate and sodium hydrogencarbonate, or an organic base such astriethylamine, pyridine, dimethylaniline and 1,4-diazabicyclo2.2.2!octane (DABCO) may be used in an amount of 1 to 10 equivalents.The reaction temperature ranges from -30 to 100° C. Examples of thesolvents to be employed include halogenated hydrocarbons (e.g. methylenechloride, chloroform and dichloroethane), ethers (e.g. diethylether andtetrahydrofuran), esters (e.g. methyl acetate and ethyl acetate), andaprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl sulfoxideand acetonitrile). The reaction time ranges usually from 10 minutes to24 hours, preferably from 0.5 to 6 hours.

The reaction between the compound (VIII) and the compound of G² --CO--R⁵in the method B is conducted, for example, under conditions similar tothose of the reaction between the compound (VIII) and the compound G¹--SO₂ --R⁴ in the method A.

The reaction between the compound (VIII) and the compound G³ --COO--R⁶in the method C is conducted, for example, under conditions similar tothose of the reaction between the compound (VIII) and the compound G¹--SO₂ --R⁴ in the method A.

The reaction between the compound (VIII) and the compound of G⁴--CO--N(R⁷)R⁸ in the method D is conducted, for example, underconditions similar to those of the reaction between the compound (VIII)and the compound G¹ --SO₂ --R⁴ in the method A.

In the reaction between the compound (IX) and the compound R² --E¹ inthe method E, the compound R² --E¹ is used in an amount ranging from oneequivalent to a large excess (1 to 10 equivalents) relative to thecompound (IX). And, a basic compound such as sodium hydroxide, potassiumhydroxide, sodium hydride, potassium carbonate, triethylamine,diisopropylethylamine and 1,8-diazabicyclo 5.4.0!-7-undecene mayoptionally be used in an amount of 1 to 10 equivalents. The reactiontemperature ranges from -20 to 200° C. Examples of the solvent to beemployed include water, lower alcohols (e.g. methanol, ethanol andpropanol), ketones (e.g. acetone and methyl ethyl ketone), ethers (e.g.tetrahydrofuran) and aprotic polar solvents (e.g. N,N-dimethylformamideand dimethyl sulfoxide). For the said reaction, as a reaction promoter,sodium iodide may be added in an amount ranging from 1 equivalent to alarge excess (1 to 10 equivalents). The reaction time ranges usuallyfrom 10 minutes to 24 hours, preferably from 0.5 to 6 hours.

The reaction between the compound (X) and the compound (XI) in themethod F is conducted, for example, under conditions similar to those ofthe reaction between the compound (IX) and the compound R² --E¹ in themethod E.

The reaction between the compound (XII) and the compound (XIII) in themethod G is conducted, for example, under conditions similar to those ofthe reaction between the compound (IX) and the compound R² --E¹ in themethod E.

For the trichloroacetylation of the compound (XIV) in the method H,trichloroacetyl chloride or anhydrous trichloroacetate is used in anamount ranging from one equivalent to a large excess (1 to 10equivalents) relative to the compound (XIV). In this case, 1 to 10equivalents of an inorganic base (e.g. potassium carbonate and sodiumhydrogencarbonate) or an organic base (e.g. 4-N,N-dimethylaminopyridine,triethylamine, pyridine, dimethylaniline and 1,4-diazabicyclo2.2.2!octane) may optionally be employed. The reaction temperatureranges from 0 to 100° C. Examples of the solvent then employed includehalogenated hydrocarbons (e.g. methylene chloride, chloroform anddichloroethane), ethers (e.g. diethyl ether and tetrahydrofuran), esters(e.g. methyl acetate and ethyl acetate) and aprotic polar solvents (e.g.N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile). Thereaction time ranges usually from 10 minutes to 100 hours, preferablyfrom 3 to 24 hours. The above-mentioned deprotection reactions of theprotective group of secondary amino group are all per se knownreactions, which can be conducted in according to known conditions. Forexample, the benzyloxycarbonyl group or the benzyl group as theamino-protecting group can be removed by catalytic reduction (reactiontemperatures ranging from room temperature to 100° C.) in a solvent(e.g. alcohol, acetic acid, water, tetrahydrofuran and an appropriatemixture of them) in the presence of a catalyst (e.g. palladium carbon orplatinum oxide). In the case of trityl group or tert-butoxycarbonylgroup, it can be removed by the reaction in a solvent (e.g. water,alcohol, tetrahydrofuran and dioxane) in the presence of an acid (e.g. amineral acid such as hydrochloric acid, phosphoric acid and sulfuricacid or an organic acid such as toluenesulfonic acid, methansulfonicacid and acetic acid), at temperatures ranging from 0 to 150° C. And, inthe case of tert-butoxycarbonyl group, it can be removed by processingwith, for example, iodotrimethylsilane in a solvent such as chloroform.Further, trifluoroacetyl group can be easily removed by treating withalkali (e.g. an aqueous solution of sodium hydroxide or sodiumhydrogencarbonate). The ring-closure reaction can be conductedconcurrently with the reaction of removing the protecting group. Or,after removing the protecting group, the ring-closure reaction can beconducted by using 1 to 10 equivalents of an inorganic base (e.g.potassium carbonate and sodium hydrogencarbonate) or an organic base(e.g. 4-N,N-dimethylaminopyridine, triethylamine, pyridine,dimethylaniline and 1,4-diazabicyclo 2.2.2!octane. The reactiontemperatures ranges from 0 to 100° C. Examples of the solvent thenemployed include halogenated hydrocarbons (e.g. methylene chloride,chloroform and dichloroethane), ethers (e.g. diethyl ether andtetrahydrofuran), esters (e.g. methyl acetate and ethyl acetate) andaprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl sulfoxideand acetonitrile). The reaction time ranges usually from 10 minutes to24 hours, preferably from 10 minutes to 6 hours.

For the ring-closure reaction by Mannich reaction using the compound(XV) and formalin in the method I, formalin is used in an amount oflarge excess (2 to 20 equivalents) relative to the compound (XV). Thereaction temperature ranges from -20 to 150° C. Examples of the solventthen used include water, lower alcohols (e.g. methanol, ethanol,propanol and isopropanol) and lower fatty acids (e.g. acetic acid andpropionic acid). The reaction time ranges usually from 10 minutes to 24hours, preferably from 10 minutes to 3 hours.

The reaction between the compound (XVI) and the compound (XVII) in themethod J is conducted, for example, under conditions similar to those ofthe reaction between the compound (VIII) and the compound G¹ -SO₂ --R⁴in the method A.

The conversion of the compound (XIX) to the thiolactam in the method Kcan be conducted with, for example, one equivalent to a large excess (1to 10 equivalents) of phosphorus pentachloride relative to the compound(XIX). The reaction temperature ranges from 0 to 200° C. Examples of thesolvent then employed include aromatic hydrocarbons (e.g. benzene,toluene and xylene) and pyridine. The reaction time ranges usually from30 minutes to 24 hours, preferably from 1 to 12 hours.

The reaction for removing the amino-protective group of the compound(XX) in the method L can be conducted, for example, under conditionssimilar to removing the amino-protecting group in the method H.

The compound (VIII) can be synthesized by, for example, the followingmethods. (i) ##STR60## wherein the symbols are of the same meanings asdefined above.

The reaction between the compound (X) and the compound (XXI) isconducted under conditions similar to those of the reaction between thecompound (X) and the compound (XI) in the method F. (ii) ##STR61##wherein the symbols are of the same meanings as defined above.

The reaction between the compound (XII) and the compound (XXII) isconducted under conditions similar to those of the reaction between thecompound (XII) and the compound (XIII) in the method G. And, thereaction for removing the amino-protective group is conducted underconditions similar to those of removing the protective group in themethod H.

The compound (IX) can be synthesized by, for example, the followingmethod. ##STR62## wherein the symbols are of the same meanings asdefined above.

The reaction between the compound (XXIII) and G¹ --SO₂ --R⁴ isconducted, for example, under conditions similar to those of thereaction between the compound (VIII) and G¹ --SO₂ --R⁴ in the method A.The reaction between the compound (XXIII) and G² --CO--R⁵ is conducted,for example, under conditions similar to those of the reaction betweenthe compound (VIII) and G² --CO--R⁵ in the method B. The reactionbetween the compound (XXIII) and G³ --COO--R⁶ is conducted, for example,under conditions similar to those of the reaction between the compound(VIII) and G³ --COO--R⁶ in the method C. The reaction between thecompound (XXIII) and G⁴ --CO--N(R⁷)R⁸ is conducted, for example, underconditions similar to those of the reaction between the compound (VIII)and G⁴ --CO--N(R⁷)R⁸ in the method D.

The compound (X) can be synthesized by, for example, the followingmethod. ##STR63## wherein the symbols are of the same meanings asdefined above.

The reaction between the compound (XII) and the compound (XXIV) isconducted, for example, under conditions similar to those of thereaction between the compound (XII) and the compound (XIII) in themethod G.

The compound (XII) can be synthesized by, for example, the followingmethod. ##STR64## wherein the symbols are of the same meanings asdefined above.

The cyclization of the compound (XXV), can be conducted with oneequivalent to a large excess (1 to 10 equivalents) of a base such assodium hydride, potassium hydride or lithium diisopropyl amide relativeto one equivalent of the compound (XXV). The reaction temperature rangesfrom -20 to 150° C. The solvent then employed is exemplified by ethers(e.g. tetrahydrofuran and dioxane) and aprotic polar solvents (e.g.N,N-dimethylformamide and dimethyl sulfoxide). The reaction time rangesusually from 10 minutes to 6 hours, preferably from 0.5 to 3 hours. (ii)##STR65## wherein the symbols are of the same meanings as defined above.

The ring-closure reaction of the compound (XXVII) is conducted, forexample, under conditions similar to those of the ring-closure reactionof the compound (XV) in the method I. And, the reaction for removing theamino-protecting group is conducted, for example, under conditionssimilar to those of the reaction of removing the protective group in themethod H. (iii) ##STR66## wherein the symbols are of the same meaningsas defined above.

The trichloroacetylation, removal of the protective group andring-closure reaction of the compound (XXVII) are conducted, forexample, under conditions similar to those for the trichloroacetylation,removal of the protective group and ring-closure reaction of thecompound (XIV) in the method H. (iv) ##STR67## wherein the symbols areof the same meanings as defined above.

The ring-closure reaction of the compound (XVI), can be conducted with,for example, one equivalent to a large excess amount (1 to 100equivalents) of aqueous ammonia relative to one equivalent of thecompound (XVI). The reaction temperature ranges from 0 to 150° C. Thesolvent then employed is exemplified by water, lower alcohols (e.g.methanol, ethanol, propanol and isopropanol), halogenated hydrocarbons(e.g. methylene chloride, chloroform and dichloroethane), ethers (e.g.tetrahydrofuran and dioxane), esters (e.g. methyl acetate and ethylacetate), and aprotic polar solvents (e.g. N,N-dimethylformamide anddimethyl sulfoxide). The reaction temperature ranges usually from 10minutes to 24 hours, preferably from 3 to 12 hours.

The compound (XIV) can be synthesized by, for example, the followingmethod.

(i) When j is 1; ##STR68## wherein the symbols are of the same meaningsas defined above.

The reaction between the compound (XXXI) and the compound (XVII) isconducted, for example, under conditions similar to those of thereaction between the compound (X) and the compound (XI) in the method F.The reaction for introducing the amino-protecting group is a per seknown reaction such as the above-mentioned deprotection of the aminogroup, which can be conducted according to known conditions.

(ii) When j is 0 and J is a hydrogen atom; ##STR69## wherein E² standsfor, for example, a halogen (e.g. chlorine, bromine and iodine), and theother symbols are of the same meanings as defined above.

The reaction between the compound (XXXII) and the compound (XVII) isconducted, for example, under conditions similar to those of thereaction between the compound (X) and the compound (XI) in the method F.(iii) When j is 0, and, J and R² are both a hydrogen atom; ##STR70##wherein the symbols are of the same meanings as defined above.

The reaction between the compound (XXXII) and the compound (XXXIV) isconducted, for example, under conditions similar to those of thereaction between the compound (X) and the compound (XI) in the method F.Introduction of R³ is conducted, for example, under conditions similarto those of the reaction between the compound (VIII) and G¹ --SO₂ --R⁴in the method A, those of the reaction between the compound (VIII) andG² --CO--R⁵ in the method B, those for the reaction between the compound(VIII) and G³ --COO--R⁶ in the method C and those for the reactionbetween the compound (VIII) and G⁴ --CO--N(R⁷)R⁸ in the method D.

(iv) When j is 1 and R² is a hydrogen atom; ##STR71##

The reaction between the compound (XXXI) and the compound (XXXIV) andthe introduction of R³ are conducted under conditions similar to thoseof the reaction between the compound (XXXII) and the compound (XXXIV)and for the introduction of R³ described in (iii) above.

The reactions for introducing the amino-protecting group are all per seknown ones as described above, for example, and they can be conductedaccording to the conditions of them.

The compound (XV) can be synthesized by, for example, the followingmethods. (i) ##STR72## wherein the symbols are of the same meanings asdefined above.

The reaction between the compound (XXXI) and the compound (XVII) isconducted, for example, under conditions similar to those of thereaction between the compound (X) and the compound (XI) in the method F.(ii)

When R² is a hydrogen atom; ##STR73## wherein the symbols are of thesame meanings as defined above.

The reaction between the compound (XXXI) and the compound (XXXIV) isconducted, for example, under conditions similar to those of thereaction between the compound (X) and the compound (XI) in the method F.Introduction of R³ is conducted, for example, under conditions similarto those of the reaction between the compound (VIII) and G¹ --SO₂ --R⁴in the method A, those of the reaction between the compound (VIII) andG² --CO₂ --R⁵ in the method B, those of the reaction between thecompound (VIII) and G³ --COO--R⁶ in the method C and those of thereaction between the compound (VIII) and G⁴ --CO--N(R⁷)R⁸ in the methodD.

The compound (XVI) can be synthesized by, for example, the followingmethod. ##STR74## wherein the symbols are of the same meanings asdefined above.

Trichloroacetylation of the compound (XXXVIII) is conducted, forexample, under conditions similar to those of trichloroacetylation ofthe compound (XIV) in the method H.

The compound (XXIII) can be synthesized by the following methods. (i)##STR75## wherein the symbols are of the same meanings as defined above.

The reaction between the compound (XII) and the compound (XL) isconducted, for example, under conditions similar to those of thereaction between the compound (XII) and the compound (XIII) in themethod G. The removal of phthalimido group, which is theamino-protecting group, can be conducted by the reaction with hydrazinehydrate in a solvent (e.g. methanol and ethanol). ##STR76## wherein thesymbols are of the same meanings as defined above.

The reaction between the compound (XVI) and the compound (XXXIV) isconducted, for example, under conditions similar to those of thereaction between the compound (XVI) and the compound (XVII) in themethod J.

The compound (XXV) can be synthesized by, for example, the followingmethod. ##STR77## wherein the symbols are of the same meanings asdefined above.

For the reaction between the compound (XLI) and the compound (XLII), thecompound (XLII) is used in an amount ranging from one equivalent to alarge excess (1 to 10 equivalents) relative to one equivalent of thecompound (XLI). The reaction temperature ranges from 0 to 200° C.Examples of the solvent then employed include water, lower alcohols(e.g. methanol, ethanol and propanol), ethers (e.g. tetrahydrofuran,dimethoxyethane and dioxane), nitrites (e.g. acetonitrile andpropionitrile) and aprotic polar solvents (e.g. N,N-dimethylformamideand dimethyl sulfoxide). To the reaction system, may optionally beadded, as the agent for removing acid 1 to 10 equivalents of aninorganic base such as potassium carbonate and sodium hydrogencarbonate,or an organic base such as triethylamine, pyridine and dimethylaniline.The reaction time ranges usually from 10 minutes to 7 days, preferablyfrom one hour to two days.

The compound (XXVII) can be synthesized by, for example, the followingmethod. ##STR78## wherein the symbols are of the same meanings asdefined above.

The reactions for introducing primary amino group into the compound(XXXI) are all per se known ones, which can be conducted according toknown reaction conditions. For example, hexamethylene tetramine in anamount of one equivalent to a large excess (1 to 10 equivalents) is usedrelative to one equivalent of the compound (XXXI). Examples of thesolvent for this reaction include water, lower alcohols (e.g. methanol,ethanol and propanol), ethers (e.g. tetrahydrofuran, dimethoxyethane anddioxane), nitrites (e.g. acetonitrile and propionitrile) and aproticpolar solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide). Thereaction temperature ranges from 0 to 200° C. The quaternary ammoniumsalt then formed can be hydrolyzed with an acid, such as hydrochloricacid (1 to 20 equivalents). The reaction temperature ranges from 0 to100° C. The reaction time ranges usually from 10 minutes to 24 hours,preferably from 1 to 3 hours. Further, the reactions for introducing aprotective group into primary amino group are all per se known ones,which can be conducted according to known reaction conditions.

The compound (XXXI) can be synthesized by, for example, the followingmethod. ##STR79## wherein the symbols are of the same meanings asdefined above.

The reduction of the compound (XXXVIII) is conducted by using a reducingagent, for example, a metal hydride complex compound such as sodiumborohydride, lithium borohydride and aluminum lithium hydride or boranecomplex compounds in an amount ranging from one equivalent to a largeexcess (1 to 10 equivalents) relative to one equivalent of the compound(XXXVIII). The reaction temperature ranges from -20 to 100° C. Examplesof the solvent employed for this reaction include alcohols (e.g.methanol and ethanol) and ethers (e.g. ethyl alcohol, tetrahydrofuranand dioxane). The reaction time ranges usually from 10 minutes to 24hours, preferably from 0.5 to 6 hours. The conversion of hydroxyl groupto E¹ is conducted, when E¹ is halogen atom, by allowing 1 to 5equivalents of a halogenating agent, for example, phosphorus halogenidesuch as phosphorus trichloride, phosphorus oxychloride, phosphoruspentachloride and phosphorus tribromide, a mixture of red phosphorus andhalogen, or thionyl chloride to react with one equivalent of an alcoholcompound. When E¹ is toluenesulfonyloxy group or methanesulfonyloxygroup, 1 to 5 equivalents of toluenesulfonyl chloride or methanesulfonylchloride is allowed to react with one equivalent of an alcohol compound.In this case, 1 to 10 equivalents of, for example, an inorganic basesuch as potassium carbonate and sodium hydrogencarbonate or an organicbase such as 4-N,N-dimethylaminopyridine, triethylamine, pyridine,dimethyl aniline and 1,4-diazabicyclo 2.2.2!octane may optionally beused. The reaction temperature ranges from 0 to 100° C. Examples of thesolvent used in this case include halogenated hydrocarbons (e.g.methylene chloride, chloroform and dichloroethane), water, ethers (e.g.diethyl ether and tetrahydrofuran), esters (e.g. methyl acetate andethyl acetate) and aprotic polar solvents (e.g. N,N-dimethylformamide,dimethyl sulfoxide and acetonitrile). The reaction time ranges usuallyfrom 10 minutes to 100 hours, preferably from 3 to 24 hours.

The compound (XXXII) can be synthesized by, for example, the followingmethod. ##STR80## wherein the symbols are of the same meanings asdefined above.

The reaction between the compound (XLIII) and the compound (XLIV) can beconducted under conditions similar to those of the reaction between thecompound (XLI) and the compound (XLII) in the above-mentioned method ofsynthesizing the compound (XXV).

The compound (XXXVIII) can be synthesized by, for example, the followingmethod. ##STR81## wherein the symbols are of the same meanings asdefined above.

The reaction between the compound (XLV) and the compound (XLIV) can beconducted under conditions similar to those of the reaction between thecompound (XLI) and the compound (XLII) in the above-mentioned method forsynthesizing the compound (XXV).

The compound (A) or a salt thereof of the present invention can besynthesized by, for example,

(1) a process for producing the compound (A) or a salt thereof whichcomprises reacting a compound of the formula: ##STR82## wherein allsymbols are of the same meanings as defined above, or a salt thereof,with a compound of the formula: ##STR83## wherein all symbols are of thesame meanings as defined above, or a salt thereof,

(2) a process for producing the compound (A) or a salt thereof whichcomprises reacting a compound of the formula: ##STR84## wherein allsymbols are of the same meanings as defined above, or a salt thereof,with a compound of the formula: G¹ --R³

wherein all symbols are of the same meanings as defined above, or a saltthereof,

(3) a process for producing the compound (A) or a salt thereof (J is 0)which comprises reacting a compound of the formula: ##STR85## whereinall symbols are of the same meanings ad defined above, or a saltthereof, with a compound of the formula: ##STR86## wherein all symbolsare of the same meanings as defined above, or a salt thereof,

(4) a process for producing the compound (A) or a salt thereof (J is 1)which comprises reacting a compound of the formula: ##STR87## whereinR^(a) C₁₋₆ alkyl group (e.g. methyl, ethyl, propyl, isopropyl), and theother symbols are of the same meanings as defined above, or a saltthereof, with a compound of the formula: ##STR88## wherein all symbolsare of the same meanings as defined above, or a salt thereof,

(5) a process for producing the compound (A) or a salt thereof whichcomprises subjecting a compound of the formula: ##STR89## wherein allsymbols are of the same meanings as defined above, or a salt thereof totrichloroacetylation, and then in case of need, deprotection of theprotecting group J, and further subjecting the resultant compound toring-closure reaction,

(6) a process for producing the compound (A) or a salt thereof whichcomprises subjecting a compound of the formula: ##STR90## wherein allsymbols are of the same meanings as defined above, or a salt thereof toring-closure reaction by using Mannich reaction, and

(7) a process for producing the compound (A) or a salt thereof (J is 0)which comprises reacting a compound of the formula: ##STR91## whereinR^(b) and R^(c) are respectively C₁₋₆ alkyl group (e.g. methyl, ethyl,propyl, isopropyl), Hal is a halogen atom (e.g. chlorine, bromine,iodine), ring Q is of the same meaning as defined above, or a saltthereof, with a compound of the formula: ##STR92## wherein all symbolsare of the same meanings as defined above, or a salt thereof.

A method of producing the compound (A) or a salt thereof, or thesatarting compound for producing it is as follow.

Method M: ##STR93## (wherein all symbols are of the same meanings asdefined above) Method N: ##STR94## (wherein all symbols are of the samemeanings as defined above) Method O: ##STR95## (wherein all symbols areof the same meanings as defined above) Method P: ##STR96## (wherein allsymbols are of the same meanings as defined above) Method Q: ##STR97##(wherein all symbols are of the same meanings as defined above) MethodR: ##STR98## (wherein all symbols are of the same meanings as definedabove) Method S: ##STR99## (wherein all symbols are of the same meaningsas defined above) Method T: ##STR100## (wherein all symbols are of thesame meanings as defined above) Method U: ##STR101## (wherein allsymbols are of the same meanings as defined above)

In the reaction between the compound (B) and the compound (C) in themethod M for producing the compound (A), one equivalent to a largeexcess amount (1 to 10 equivalents) of the compound (C) is employedrelative to the compound (B). In this case, a basic compound such assodium hydroxide, potassium hydroxide, sodium hydride, potassiumcarbonate, triethylamine, diisopropylethylamine 1,4-diazabicyclo2.2.2!octane and 1,8-diazabicyclo 5.4.0!-7-undecene may be used in anamount of 1 to 10 equivalents. The reaction temperature ranges from -20to 200° C. Examples of the solvents to be employed include water, loweralcohols (e.g. methanol, ethanol and propanol), ketones (e.g. acetoneand methyl ethyl ketone), ethers (e.g. tetrahydrofuran) and aproticpolar solvents (e.g. N,N-dimethylformamide and dimethylsulfoxide). Forthe said reaction, as a reaction-promoting agent, sodium iodide may beadded in an amount ranging from one equivalent to a large excess (1 to10 equivalents). The reaction time ranges usually from 10 minutes to 24hours, preferably from 0.5 to 6 hours.

In the reaction between the compound (D) and the compound: G¹ --SO₂ --R⁴in the method N, one equivalent to a large excess amount (1 to 10equivalents) of the compound: G¹ --SO₂ --R⁴ is employed relative to thecompound (D). In this case, an inorganic base such as potassiumcarbonate and sodium hydrogencarbonate, or an organic base such astriethylamine, pyridine, dimethylaniline, 1,4-diazabicyclo 2.2.2!octane(DABCO), or 1,8-diazabicyclo 5.4.0!-7-undecene may be used in an amountof 1 to 10 equivalents. The reaction temperature ranges from -30 to 100°C. Examples of the solvents to be employed include halogenatedhydrocarbons (e.g. methylene chloride, chloroform and dichloroethane),ethers (e.g. diethylether and tetrahydrofuran), esters (e.g. methylacetate and ethyl acetate) and aprotic polar solvents (e.g.N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile). Thereaction time ranges usually from 10 minutes to 24 hours, preferablyfrom 0.5 to 6 hours.

The reaction between the compound (D) and the compound: G² --CO--R⁵ inthe method O is conducted, for example, under conditions similar tothose of the reaction between the compound (D) and the compound: G¹--SO₂ --R⁴ in the method N.

The reaction between the compound (D) and the compound: G³ --COO--R⁶ inthe method P is conducted, for example, under conditions similar tothose of the reaction between the compound (D) and the compound: G¹--SO₂ --R⁴ in the method N.

The reaction between the compound (E) and the compound (F) in the methodQ is conducted, for example, under conditions similar to those of thereaction between the compound (B) and the compound (C) in the method M.

The reaction between the compound (G) and the compound (F) in the methodR is conducted, for example, under conditions similar to those of thereaction between the compound (B) and the compound (C) in the method M.

For the trichloroacetylation of the compound (H) in the method S,trichloroacetyl chloride or anhydrous trichloroacetate is used in anamount ranging from one equivalent to a large excess (1 to 10equivalents) relative to the compound (H). In this case, 1 to 10equivalents of an inorganic base (e.g. potassium carbonate and sodiumhydrogencarbonate) or an organic base (e.g. 4-N,N-dimethylaminopyridine,triethylamine, pyridine, dimethylaniline and 1,4-diazabicyclo2.2.2!octane, 1,8-diazacyclo 5.4.0!-7-undene) may optionally beemployed. The reaction temperature ranges from 0 to 100° C. Examples ofthe solvent then employed include halogenated hydrocarbons (e.g.methylene chloride, chloroform and dichloroethane), ethers (e.g. diethylether and tetrahydrofuran), esters (e.g. methyl acetate and ethylacetate) and aprotic polar solvents (e.g. N,N-dimethylformamide,dimethyl sulfoxide and acetonitrile). The reaction time ranges usuallyfrom 10 minutes to 100 hours, preferably from 3 to 24 hours. Theabove-mentioned deprotection reactions of the protective group ofsecondary amino group represented by J, are all per se known reactions,which can be conducted in according to known conditions. For example,the benzyloxycarbonyl group or the benzyl group as the amino-protectinggroup can be removed by catalytic reduction (reaction temperaturesranging from room temperature to 100° C.) in a solvent (e.g. alcohol,acetic acid, water, tetrahydrofuran and an appropriate mixture of them)in the presence of a catalyst (e.g. palladium carbon or platinum oxide).In the case of trityl group or tert-butoxycarbonyl group, it can beremoved by the reaction in a solvent (e.g. water, alcohol,tetrahydrofuran and dioxane) in the presence of an acid (e.g. a mineralacid such as hydrochloric acid, phosphoric acid and sulfuric acid or anorganic acid such as toluenesulfonic acid, methansulfonic acid andacetic acid), at temperatures ranging from 0 to 150° C. And, in the caseof tert-butoxycarbonyl group, it can be removed by processing with, forexample, iodotrimethylsilane in a solvent such as chloroform. Further,trifluoroacetyl group can be easily removed by treating with an alkali(e.g. an aqueous solution of sodium hydroxide or sodiumhydrogencarbonate). The ring-closure reaction can be conductedconcurrently with the reaction of removing the protecting group. Or,after removing the protecting group, the ring-closure reaction can beconducted by using 1 to 10 equivalents of an inorganic base (e.g.potassium carbonate and sodium hydrogencarbonate) or an organic base(e.g. 4-N,N-dimethylaminopyridine, triethylamine, pyridine,dimethylaniline, 1,4-diazabicyclo 2.2.2!octane and 1,8-diazacyclo5.4.0!-7-undene). The reaction temperatures ranges from 0 to 100° C.Examples of the solvent then employed include halogenated hydrocarbons(e.g. methylene chloride, chloroform and dichloroethane), ethers (e.g.diethyl ether and tetrahydrofuran), esters (e.g. methyl acetate andethyl acetate) and aprotic polar solvents (e.g. N,N-dimethylformamide,dimethyl sulfoxide and acetonitrile). The reaction time ranges usuallyfrom 10 minutes to 24 hours, preferably from 10 minutes to 6 hours. Forthe ring-closure reaction by Mannich reaction using the compound (J) andformalin in the method T, formalin is used in an amount of large excess(2 to 20 equivalents) relative to the compound (J). The reactiontemperature ranges from -20 to 150° C. Examples of the solvent usedinclude water, lower alcohols (e.g. methanol, ethanol, propanol andisopropanol) and lower fatty acids (e.g. acetic acid and propionicacid). The reaction time ranges usually from 10 minutes to 24 hours,preferably from 10 minutes to 3 hours.

In the reaction between the compound (K) and the compound (F) in themethod U of producing the compound (A), one equivalent to a large excessamount (1 to 10 equivalents) of the compound (F) is employed relative tothe compound (K). In this case, sodium hydroxide, potassium hydroxide,sodium hydride, potassium carbonate, triethylamine,diisopropylethylamine, 1,4-diazabicyclo 2.2.2!octane or 1,8-diazabicyclo5.4.0!-7-undene may be used in an amount of 1 to 10 equivalents. Thereaction temperature ranges from -20 to 200° C. Examples of the solventsto be employed include water, lower alcohols (e.g. methanol, ethanol,propanol, isopropanol), ethers (e.g. diethylether, tetrahydrofuran),estels (e.g. methyl acetate, ethyl acetate) and aprotic polar solvents(e.g. N,N-dimethylformamide, dimethylsulfoxide). The reaction timeranges usually from 0.5 to 96 hours, preferably from 6 to 24 hours.

The compound (B) can be synthesized by using the similar method ofproducing the compound (II).

The oxo group on ring A^(a) of the compound (B) can be reduced asfollow. ##STR102## (wherein ring Q is of the same meaning as definedabove)

In the reduction of the compounds (L) and (M), one equivalent to a largeexcess amount (1 to 10 equivalents) of metal hydride complex compound(e.g. sodium boron hydride, lithium boron hydride, lithium aluminumhydride) or borane complex compound is employed relative to thecompounds (L) or (M). In this case, alcohols (e.g. methanol, ethanol)and ethers (e.g. ethylether, tetrahydrofuran, dioxane) may be used asthe solvent.

The reaction temperature ranges from -10 to 100° C. The reaction timeranges usually from 10 minutes to 24 hours, preferably from 0.5 to 6hours.

The compound (D) can be synthesized by following methods and so on.##STR103## (wherein R^(d) is a hydrogen atom or a protective group ofamino group (e.g. benzyloxycarbonyl, tert-butoxycarbonyl,trifluoroacetyl, trityl, benzyl), and the other symboles are of the samemeanings as defined above)

The reaction between the compound (B) and the compound (N) is conducted,for example, under conditions similar to those of the reaction betweenthe compound (B) and the compound (C) in the method M. Removal ofprotective group R^(d) of secondary amino group is a per se knownreaction and so on. ##STR104## (wherein R^(e) is a hydrogen atom or aprotective group of amino group (e.g. benzyloxycarbonyl,tert-butoxycarbonyl, trifluoroacetyl, trityl, benzyl), and the othersymbols are of the same meanings as defined above)

The reaction between the compound (E) and the compound (O) is conducted,for example, under conditions similar to those of the reaction betweenthe compound (B) and the compound (C) in the method M. Removal ofprotective group R^(e) of secondary amino group is a per se knownreaction and so on. ##STR105## (wherein all symbols are of the samemeanings as defined above)

The reaction between the compound (G) and the compound (O) is conducted,for example, under conditions similar to those of the reaction betweenthe compound (B) and the compound (C) in the method M.

Removal of protective group R^(e) of secondary amino group is a per seknown reaction and so on. ##STR106## (wherein all symbols are of thesame meanings as defined above)

The trichloroacetylation of the compound (P) is conducted, for example,under conditions similar to those of the trichloroacetylation of thecompound (H) in the method S. Removal of protective group J of secondaryamino group is conducted, for example, under conditions similar to thoseof the removal of protective group of amino group in the method S.

The ring-closure reaction is conducted, for example, under conditionssimilar to those of the ring-closure reaction in the method S. Removalof R^(e) is a per se known reaction and so on. ##STR107## (wherein allsymbols are of the same meanings as defined above)

The Mannich reaction of the compound (Q) is conducted, for example,under conditions similar to those of the Mannich reaction of thecompound (J) in the method T. Removal of protective group R^(e) ofsecondary amino group is a per se known reaction and so on. ##STR108##(wherein all symbols are of the same meanings as defined above)

The reaction between the compound (K) and the compound (O) is conducted,for example, under conditions similar to those of the reaction betweenthe compound (K) and the compound (F) in the method U. Removal ofprotective group R^(e) of secondary amino group is a per se knownreaction and so on.

The compounds (L) and (M) can be synthesized by the similar methods forproducing the compound (XII) such as the compounds (XXVI), (XXVIII) and(XXIX) as described above.

The compound (G) can be synthesized be the following method. ##STR109##(wherein all symbols are of the same meanings as defined above)

The reaction for introducing E¹ into the compound (R) is a per se knownreaction and so on. For example, chlorine, bromine, tert-butylhypohalogerite, N-halogenosuccinimido (e.g. N-bromosuccinimido),N-bromocaprolactam, N-bromophthalimido,1,3-dibromo-5,5-dimethylhydantoin, trichloromethanesulfonyl halide (e.g.trichloromethanesulfonylchloride), tribromomethane and phosphoruspentachloride are used in the halogenation reaction. For the reaction,addition of a peroxide (e.g. benzoyl peroxide) or an optical irradiatefor promoting the reaction promotor may be used. The reactiontemperature ranges from -20 to 200° C., and the reaction time rangesusually from 0.5 to 6 hours. In this case, solvents, such as aromatichydrocarbons (e.g. benzene), halogenated hydrocarbons (e.g. methylenechloride, chloroform, dichloroethane), saturated hydrocarbons (e.g.hexane, heptane, cyclohexane), esters (e.g. methyl acetate, ethylacetate) may be used.

The compound (H) can be synthesized by the following method. ##STR110##(wherein all symbols are of the same meanings as defined above)

The reaction for introducing protective group J into amino group on thecompound (J) is a per se known reaction and so on.

The compound (P) can be synthesized by the following method. ##STR111##(wherein all symbols are of the same meanings as defined above)

The reaction for introducing protective group J into amino group on thecompound (Q) is a per se known reaction and so on.

The compound (J) can be synthesized by the following method. ##STR112##)wherein all symbols are of the same meanings as defined above)

The reaction between the compound (S) and the compound (F) is conducted,for example, under conditions similar to those of the reaction betweenthe compound (B) and the compound (C) in the method M.

The compound (Q) can be synthesized by the following method. ##STR113##(wherein all symbols are of the same meanings as defined above)

The reaction betwen the compound (S) and the compound (O) is conducted,for example, under conditions similar to those of the reaction betwenthe compound (B) and the compound (C) in the method M.

The compound (K) can be synthesized by the following method. ##STR114##

In the dialkylaminomethylation of the compound (T), one equivalent to alarge excess amount (1 to 10 equivalents) of N,N-dimethyleneammoniumiodide is employed relative to the compound (T). The reactiontemperature ranges from 0 to 100° C., and the reaction time rangesusually from 0.5 hour to 24 hours, preferably from 1 to 6 hours.Examples of the solvents to be employed include, for example,halogenated hydrocarbons (e.g. methylene chloride, chloroform, carbontetrachloride, dichloroethane), ethers (e.g. diethylether,tetrahydrofuran), esters (e.g. methyl acetate, ethyl acetate) andaprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide,acetonitrile).

In the quaternarization, one equivalent to a large excess amount (1 to10 equivalents) of C₁₋₆ alkyl halide such as methyl iodide is employedrelative to the dialkylaminomethyl compound. The reaction temperatureranges from 0 to 100° C., and the reaction time ranges usually from 1 to100 hours, preferably 6 to 24 hours. Examples of the solvents to beemployed include, for example, halogenated hydrocarbons (e.g. methylenechloride, chloroform, carbon tetrachloride, dichloroethane), ethers(e.g. diethylether, tetrahydrofuran), estes (e.g. methyl acetate, ethylacetate) and aprotic polar solvents (e.g. N,N-dimethylformamide,dimethylsulfoxide, acetonitrile).

The compound (S) can be synthesized by the following method. ##STR115##(wherein all symbols are of the same meanings as defined above)

In the reduction of the compound (T), one equivalent to a large excessamount (1 to 10 equivalents) of metal hydride complex compound (e.g.sodium boron hydride, lithium boron hydride, lithium alminum hydride) orborane complex compound is employed relative to the compound (T). Thereaction temperature ranges from -20 to 100° C., and the reaction timeranges usually from 10 minutes to 24 hours, preferably 0.5 to 6 hours.Examples of the solvents to be employed include, for example, alcohols(e.g. methanol, ethanol), ethers (e.g. diethylether, tetrahydrofuran,dioxane).

In the conversion from hydroxyl group to E¹ (e.g. halogen), 1 to 5equivalents of halogenated phosphorus (e.g. phosphorus trichloride,phosphorus oxychloride, phosphorus pentachloride, phosphorustribromide), halogenation agent (e.g. red phosphorus and halogen,thionyl chloride) are employed relative to the alcohol compound.

In the conversion from hydroxyl group to E¹ (e.g. p-toluenesulfonyloxy,methanesulfonyloxy), 1 to 5 equivalents of p-toluensulfonylchloride ormethanesulfonyl chloride are employed relative to the alcohol compound.In this case, an inorganic base such as potassium carbonate, sodiumhydrogencarbonate, an organic base such as 4-N,N-dimethylaminopyridine,triethylamine, pyridine, dimethylamiline, 1,4-diazabicyclo 2.2.2!octane,1,8-diazabicyclo 5.4.0!-7-undecene may be used in an amount of 1 to 10equivalents. The reaction temperature ranges from 0 to 100° C., and thereaction time ranges usually from 10 minutes to 100 hours, preferablyfrom 3 to 24 hours. Examples of the solvents to be employed include, forexample, halogenated hydrocarbons (e.g. methylene chloride, chloroform,dichloroethane), water, ethers (e.g. diethylether, tetrahydrofuran),esters (e.g. methyl acetate, ethyl acetate) and aprotic polar solvents(e.g. N,N-dimethylformamide, dimethylsulfoxide, acetonitrile).

The compound (T) can be synthesized by the following method. ##STR116##(wherein all symbols are of the same meanings as defined above)

In the reaction between the compound (U) and the compound: E¹ CH₂ CHO,one equivalent to a large excess amount (1 to 10 equivalents) of thecompound of the compound (Y) is employed relative to the compound (U).The reaction temperature ranges from 0 to 200° C., and the reaction timeranges usually from 10 minutes t 24 hours, preferably 0.5 to 6 hours.Examples of the solvents to be employed include, for example,halogenated hydrocarbons (e.g. methylene chloride, chloroform,dichloroethane), water, alcohols (e.g. methanol, ethanol), ethers (e.g.diethylether, tetrahydrofuran, dioxane), esters (e.g. methyl acetate,ethyl acetate) and aprotic polar solvents (e.g. N,N-dimethylformamide,dimethylsulfoxide, acetonitrile).

The compound (E) can be synthesized by the following method. ##STR117##(wherein all symbols are of the same meanings as defined above)

The trichloroacetylation of the compound (W) is conducted, for example,under conditions similar to those of the trichloroacetylation of thecompound (H).

The compound (W) can be synthesized by the following method. ##STR118##(wherein all symbols are of the same meanings as defined above)

The reaction between the compound (Y) and the compound: E¹ CH₂ CHO isconducted, for example, under conditions similar to those of thereaction between the compound (U) and the compound: E¹ CH₂ CHO.

The starting materials for producing the compound (I') may form a salt.The salt may be employed as similar as the salt of the compound (I').

The intermediate compounds for synthesizing the desired compound (I') ora salt obtained by the above-mentioned methods can be isolated by thefollowing conventional separation means, or reaction mixture per se mayoptionally be used, as the starting materials for the subsequent stepwithout isolation.

The isolation and purification of the compound (I') from the reactionmixture is conducted according to conventional separation means (forexample, extraction, concentration, filtration, recrystallization,column chromatography and thin-layer chromatography).

And, in each of the above-mentioned reactions, when the startingcompounds and intermediate compounds has amino group, carboxyl group orhydroxyl group as the substituent, they may have a protective groupgenerally used in the peptide chemistry. After completion of thereaction, the desired compound can be obtained by removing theprotective group upon necessity.

Examples of the amino-protecting group include optionally substitutedC₁₋₆ alkyl carbonyl (e.g. formyl, methyl carbonyl and ethyl carbonyl),phenyl carbonyl, C₁₋₆ alkyl-oxycarbonyl (e.g. methoxycarbonyl andethoxycarbonyl), phenyloxycarbonyl (e.g. benzoxycarbonyl), C₇₋₁₀aralkyloxy-carbonyl (e.g. benzyloxycarbonyl), trityl and phthaloyl.Examples of substituents of them include halogen atoms (e.g. fluoro,chloro, bromo and iodo), C₁₋₆ alkyl-carbonyl (e.g. methylcarbonyl,ethylcarbonyl and butylcarbonyl) and nitro group, and the number of thesubstituents ranges from about 1 to 3.

Examples of the carboxyl-protecting group include C₁₋₆ alkyl (e.g.methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl), phenyl,trityl and silyl. Examples of substituents of them include halogen atoms(e.g. fluorine, chlorine, bromine and iodine), C₁₋₆ alkylcarbonyl(formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitrogroup, and the number of the substituents ranges from about 1 to 3.

Examples of the hydroxyl-protecting group include for example,optionally substituted C₁₋₆ alkyl (e.g. methyl, ethyl, n-propyl,i-propyl, n-butyl and tert-butyl), phenyl, C₇₋₁₀ aralkyl (e.g. benzyl),C₁₋₆ alkylcarbonyl (e.g. formyl, methylcarbonyl and ethylcarbonyl),phenyloxycarbonyl, C₇₋₁₀ aralkyloxy-carbonyl (e.g. benzyloxycarbonyl),pyranyl, furanyl and silyl. As the substituents mentioned above, halogenatoms (e.g. fluoro, chloro, bromo and iodo), C₁₋₆ alkyl, phenyl, C₇₋₁₀aralkyl and nitro group were used. The number of substituents rangesfrom about 1 to 4.

And, the protecting groups can be introduced and removed by per se knownmeans or those analogous thereto (for example, I. F. W. McOmie et al.,PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, Plenum Press). Morespecifically, those protecting groups are removed by, for example, acid,base, reduction, ultraviolet ray, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride or palladiumacetate.

The compound (I') produced by the above-mentioned methods can beisolated and purified by a conventional separating means such asrecrystallization, distillation and chromatography. When the compound(I') thus obtained is in the free form, it can be converted to a salt byper se known means or analogous means thereto (e.g. neutralization).Conversely, when the compound (I') is obtained in the form of a salt, itcan be converted to the free form or any other salt by per se knownmeans or analogous means thereto.

Further, when the compound (I') is an optically active compound, it canbe resolved into d-isomer and 1-isomer by a conventional means foroptical resolution.

The compound (I') and the pharmaceutically acceptable salt of thepresent invention have an excellent inhibiting activity of PDGF action,antihypertensive activity, ameliorating activity of renal diseases andactivity of lowering lipid level, and are relatively less toxic.Therefore, these compounds or their salts can be safely used, in mammals(e.g. mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkeyand human), as therapeutic agents of, for used as hypertension, renaldiseases (e.g. acute renal failure, diabetic nephropathy, nephritis,mesangial proliferative glomerulonephritis, endocapillary proliferativeglomerulonephritis, membranoproliferative glomerulonephritis type I-III,crescentic glomerulonephritis, diffuse sclerosing glomerulonephritis),arteriosclerotic diseases, the other cardiovasular diseases, chronicrheumatoid arthritis, restenosis after PTCA, cancers and hyperlipemia.

While the compound (I') or a salt thereof can be administered as it is,it is usually administered in the form of preparation formulated by aconventional method using carriers or diluents for pharmaceuticalpreparations adequately selected from excipients (e.g. calciumcarbonate, kaolin, sodium hydrogencarbonate, lactose, starch,crystalline cellulose, talc, fine granulated sugar and poroussubstance), binders (e.g. dextrin, gum, alcoholated starch, gelatin,hydroxypropyl cellulose, hydroxypropyl methyl cellulose and furfuran),disintegrants (e.g. carboxymethyl cellulose calcium, closcarmellosesodium, clospovidone, low-substituted hydroxypropyl cellulose andpartial α-starch), lubricants (e.g. magnesium stearate, calciumstearate, talc, starch and sodium benzoate), colorants (e.g. tarpigment, caramel, iron sesquioxide, titanium oxide and riboflavins),flavoring agents (e.g. sweeteners and perfume), stabilizers (e.g. sodiumsulfite) and preservatives (e.g. parabens and sorbic acid) in adequateamounts respectively. The therapeutic agent of the present inventioncontaining the above-mentioned pharmaceutical preparation contains thecompound (I') or a salt thereof in a amount effective for the therapyand prophylaxis. The content of the compound (I') or a salt thereof inthe pharmaceutical preparation of the present invention ranges usuallyfrom 0.1 to 100 weight % relative to the whole weight of thepharmaceutical preparation. And, the pharmaceutical preparation of thepresent invention may contain, as active components, medicinalcomponents other than the compound (I') or a salt thereof. Thesemedicinal components are not specifically restricted so long as theobject of this invention is attained, and can be used in adequateratios. As the said "medicinal components", use is made of, for example,diuretic, angiotensin II receptor antagonist, calcium blocker, ACEinhibitor, kimase inhibitor, HMG-CoA reductase inhibitor and squalenesynthetase inhibitor. Specific examples of the formulation includetablets (including sugar-coated tablets and film-coated tablets), pills,capsules, granules, powdery preparations, syrups, emulsions,suspensions, injections, inhalants and ointments. These formulations areprepared by a conventional method (e.g. the method described in theJapanese Pharmacopeia).

More specifically, tablets can be prepared by, for example, thefollowing processes:

1) the pharmaceutical preparation as it is, or a homogeneous mixture ofthe pharmaceutical preparation with an excipient, a binder, adisintegrant or any other suitable additive, is granulated by anadequate means, to which is added, for example, a lubricant, and thewhole mixture is subjected to compression molding;

2) the pharmaceutical preparation as it is, or a homogeneous mixture ofthe pharmaceutical preparation with an excipient, a binder, adisintegrant or any other suitable additive, is directly subjected tocompression molding; or

3) the granules prepared in advance as they are, or a homogeneousmixture of the granules with a suitable additive, is subjected tocompression molding. And, to this pharmaceutical preparation, a colorantor a flavoring agent may optionally be supplemented upon necessity.Furthermore, this pharmaceutical preparation may optionally be coatedwith a coating agent.

Injectable preparations can be provided by dissolving, suspending oremulsifying a given amount of the pharmaceutical preparation in, whenusing an aqueous solvent, e.g. water for injection, physiological salineor Ringer's solution, and, when using a water-insoluble solvent, usuallye.g. vegetable oil, or by filling a given amount of the pharmaceuticalpreparation into a vessel, followed by sealing the vessel.

As the carriers for orally administrable preparations, use is made ofsubstances commonly employed in the field of pharmaceuticalpreparations, for example, starch, mannitol, crystalline cellulose andsodium carboxymethyl cellulose. As the carriers for injectablepreparations, use is made of, for example, distilled water,physiological saline solution, glucose solution and an agent ofinfusion. Besides, additives generally employed for pharmaceuticalpreparations can be adequately supplemented.

The pharmaceutical preparations of this invention are relatively lesstoxic and useful as medicinal preparations, which have PDGF-inhibitingactivity, antihypertensive activity, ameliorating activity of renaldiseases and lipid lowering activity. Therefore, the pharmaceuticalpreparations of this invention are useful as medicines for diseases dueto these pharmacological actions. The pharmaceutical preparations ofthis invention can thus be used as the therapy or prophylaxis of, amongothers, hypertension, acute renal failure, diabetic nephropathy,nephritis, arteriosclerosis, chronic rheumatoid arthritis, cancers andhyperlipemia.

The dose of the pharmaceutical preparations of this invention varieswith administration routes, symptoms, the age and body weight ofpatients and it is preferable that for treating hypertension, renaldiseases or arterioscleotic diseases a daily dose of 0.01 to 300 mg/kg,preferably 0.2 to 50 mg/kg, more preferably 5 to 30 mg/kg for oraladministration is given once or divided into several times. Theadministration route may be either oral or non-oral.

The experimental results showing the pharmacological effects of thecompound (I') or a salt thereof of this invention are described asfollows:

Test Example 1

Inhibitory effects on the contraction due to PDGF Method: The thoracicaorta of stroke prone spontaneously hypertensive rats at ages rangingfrom 16 to 36 weeks were isolated, and strip (2 mm in width, 2 cm inlength) were prepared from the aorta. Each strip was mounted in 10 ml ofan organ bath, which was loaded at 2 g and allowed to stabilized for 2to 3 hours. As the nutrient, a Krebs-Henseleit solution, bubbled with amixture gas (95% O2, 5% CO₂), was used. At the time when the contractionresponse against 60 mM KCl becomes constant, each strip was applied by1.7 nM of PDGF-AB (Cosmobio Inc.) for contraction. Observation wascontinued until the contraction become maximum and stable (30 to 40minutes after application of PDGF-AB). Then, the strips were washed,and, in about one hour later (after the tone of the vaso-contraction wasrecovered to the original level), 10 μl of the drug (DMSO solution) wasadded. Thirty minutes after drug, 1.7 nM of PDGF-AB was added again andsubjected to observation until the contraction became maximum. ThePDGF-AB-induced contraction was isometrically recorded on a polygraph(Nihon Denki San-ei). From the contractile response of the strips toPDGF-AB in the absence or presence of drugs, % inhibition of each drugwas calculated. IC₅₀ value for the inhibitory effects was calculated inaccordance with the Filler's theorem using the least squares method. Theresults are shown in Table 1.

                  TABLE 1    ______________________________________           Compound           (No. of Ex.)                   IC.sub.50 (μM)    ______________________________________           1       2.13           3       0.29           6       1.27           8       0.31           26      0.37           30      2.26    ______________________________________

From the Table 1, it is demonstrated that the compound (I') or a itssalt of the present invention has an excellent action of inhibitingPDGF-induced contraction.

Test Example 2

Antihypertensive action in spontaneously hypertensive rats (SHRs)

Method: Male SHR at ages ranging from 20 to 24 weeks were anesthetizedwith pentobarbital-sodium (50 mg/kg, i.p.) and, from the femoral arteryof each animal, a polyethylene tube was inserted. The polyethylene tubewas connected to a pressure transducer and blood pressure after oraladministration of drugs was recorded continuously under non-anesthesia.The animals, after the operation, were allowed to freely access todrinking water and eating, until administration of the drugs. Thecompounds were all orally administered as a suspension in gum arabic (2ml/kg). The results are shown in Table 2.

                  TABLE 2    ______________________________________    Antihypertensive action    Compound     dose    blood-pressure change    (No. of Ex.) (mg/kg) (mmHg)    ______________________________________     1           10      -21  after 5 hrs.!     6           10      -19  after 4 hrs.!    11           30      -31  after 7 hrs.!    26           10      -22  after 7 hrs.!    27           30      -17  after 7 hrs.!    28           30      -13  after 3 hrs.!    30           30      -17  after 7 hrs.!    35           30      -14  after 2 hrs.!    37           30      -14  after 5 hrs.!    38           30      -19  after 4 hrs.!    40           30      -20  after 7 hrs.!    ______________________________________

From Table 2, in the test groups, an antihypertensive effect of about 20mmHg as compared with the control group was observed at 2 to 7 hoursafter administration of the compound (I') or a salt thereof of thepresent invention. Therefore, the compound (I') or a salt thereof of thepresent invention was considered to have an excellent antihypertensiveaction.

Test Example 3

Antiproteinuric effect in 5/6 nephrectomized rats Method: Male SpragueDawley rats of five-week old (Japan Clea) were anesthetized withpentobarbital-sodium (50 mg/kg, i.p.), and the right kidney was excisedby dorsal incision, and its two-thirds were cut. Two weeks later, thewhole of left kidney was removed. In the Sham group, only the secondoperation was performed. In two weeks after the second operation, urinewas collected for 24 hours under drinking water ad libitum. Urinaryalbumin and total protein were quantitatively determined by the use ofA/G B-test (Wako). On the following day of collecting urine, the bloodpressure was measured by the tail cuff method. Test animals showing moreproteinuria than that of Sham group were selected. Based on the amountof the proteinuria and the blood pressure level, the animals weregrouped so that, the average and distribution of urinary protein andblood pressure same in each group. The drug was suspended ingumarabic/water or dissolved in water, and orally administered once aday for 6-8 weeks in a volume of 2 ml/kg. The administration wasconsecutively performed, and, at 2, 4, 6 and 8th weeks of treatment,urine was collected and blood pressure was measured. The vehicle groupwas orally administered with only water at a dose of 2 ml/kg. Theresults are shown in Table 3.

                  TABLE 3    ______________________________________    Antiproteinurea action    (Urinary protein excretion)    Compound         Urinary protein excretion (mg/day)    (No. of  Dose    0       2     4    6     8    Ex.)     (mg/kg) (weeks)    ______________________________________    Control          114.4   123.1 102.5                                        256.9 220.4    group     1        3      114.5   117.0 98.2 156.3 102.8     6       10      114.1   103.0 93.9 167.2 117.3    11       10      115.1   69.1  62.5 170.3 125.4    30        3      114.1   98.2  69.7 180.5 156.5    ______________________________________

                  TABLE 4    ______________________________________    Antiproteinuric action    (Urinary albumin excretion)    Compound         Urinary albumin excretion (mg/day)    (No. of  Dose    0       2     4    6     8    Ex.)     (mg/kg) (weeks)    ______________________________________    Control          10.0    29.2  30.6 54.2  69.7    group     1        3      11.2    16.9  18.4 13.0  25.1     6       10      6.8     13.5  17.2 13.1  24.8    11       10      10.2    19.8  30.3 26.0  38.3    30        3      8.6     13.9  13.2 13.5  21.0    ______________________________________

From Table 3, it is apparent that, from 4 weeks after renal ablation,urinary protein and urinary albumin in urea were remarkably increased.In contrast, in the test groups, no increase was observed in urinarytotal protein and urinary albumin. At 4th to 8th week of consecutiveadministration, the levels of urinary protein and albumin weresignificantly lower than those of the control group. Therefore, thecompound (I') or a salt thereof present the leakage of protein intourine, and its efficacy on the therapy of renal diseases such asglomerulosclerosis is expected.

Test Example 4

Cholesterol lowering effects in hamsters Method: Syrian hamsters of 10weeks old were stabilized with common feed for two weeks. The animalswere grouped based on the total cholesterol in blood. The vehicle(water) or drug was orally administered in a volume of 2 ml/kg for twoweeks. During the period of the administration, blood was collected fromretinal vessels with passage of time and the total cholesterol andtriglyceride in blood were determined. On the other hand, blood wascollected from abdominal aorta on the second week after the consecutiveadministration of the test compounds to determine the total cholesterol,triglyceride and HDL (high density lipid)-cholesterol in blood.Cholesterol C-test, triglyceride G-test and HDL-cholesterol E test (allmanufactured by Wako Pure Chemical Industries, Ltd.) were used for thedetermination of these parameters, respectively. The results are shownin Table 5.

                  TABLE 5    ______________________________________    Cholesterol-lowering action    Compound   Dose         % of Vehicle    (No. of Ex.)               (mg/kg)      TC     TC-HDL    ______________________________________     1         30           64.1   68.9     3         10           82.2   79.0     6         10           89.5   84.6     8         10           81.5   77.1    26         30           74.5   72.1    28         30           65.1   61.6    30         30           81.9   77.4    ______________________________________

From Table 5, it is apparent that, in the control group, the totalcholesterol (TC) in blood increased with the passage of time. On thecontrary, in the test groups, the increase of cholesterol in blood wassuppressed by about 20 to 30%. On the other hand, no difference wasobserved HDL-cholesterol level at the second week of the consecutiveadministration between the vehicle group and test groups. From theseresults, it is apparent that the values, total cholesterol value!-HDL-cholesterol value!; were lower in the test groups than that of thecontrol group. Therefore, the compound (I') or a salt thereof act todecrease LDL (low density lipid) and VLDL (very low density lipid) inblood, and are useful against cardivascular diseases, for example,arteriosclerosis.

Test Example 5

Experiments of urinary protein excretion in SHC rats

Method: Spontaneously hypercholesterolemic rats (male, 7 weeks old) weregiven a drug suspended in 0.5% methylcellulose (100 cP) by oraladministration once daily for 6 weeks. A control group was given 0.5%methylcellulose (100 cP) by the same route once daily.

As a normal control group, Sprague-Dawley rats (SD rats) (male, 7 weeksold, CLEA Japan, Inc.) were given 0.5% methylcellulose (100 cP) orallyonce daily.

Before the start of medication and at 2-weeks intervals after the firstadministration of drugsr urine was collected for twenty four hours andthe total protein and albumin excreted in the urine were determined. Theassay of total protein and albumin was carried out using the A/GB TestWako (Wako Pure Chemical Ind.).

The results are shown in Table 6 and Table 7.

                  TABLE 6    ______________________________________    Effect on urinary total protein excretion                     Urinary total protein (mg/day)            Dose     Duration of administration (weeks)    Group     (mg/kg/day)                         0       2     4     6    ______________________________________    Control   --         39.5    125.7 235.3 275.2    Example 83 (ii)              1          39.2    50.4  91.3  199.4    SD rat    --         19.1    45.4  53.8  38.4    ______________________________________

                  TABLE 7    ______________________________________    Effect on urinary albumin excretion                     Urinary albumin (mg/day)            Dose     Duration of administration (weeks)    Group     (mg/kg/day)                         0       2     4     6    ______________________________________    Control   --         12.1    67.1  154.7 174.4    Example 83 (ii)              1          12.0    10.9  46.2  129.9    SD rat    --         4.2     10.1  8.2   9.7    ______________________________________

Test Example 6

Experiments of PDGF-induced proliferation in Hs68 cells

Method: Human skin fibroblasts (Hs68, Institute for Fermentation, Osaka)were seeded in 48-well plates precoated with collagen type I (Falcon)(25000 cells/well), and cultured for one day. Then, the cells werecultured in Dulbecco's modified Eagle's medium (high glucose) containing0.1% bovine serum albumin for 48 hours. Fifteen (15) minutes after theaddition of the drug, the cells were stimulated with 5 ng/ml of PDGF-BB(Becton Dickinson Labware) containing ³ H-thymidine (final concentration0.4 mCi/ml) (Amersham). After 24 hours, the reaction was stopped with7.5% trichloroacetic acid at 4° C. and the plate was allowed to stand at4° C. for 30 minutes. The cells were washed with Ca^(2a) and Mg²⁺ -freephosphate-buffered saline (PBS), after then 0.1% sodium dodecyl sulfate(SDS)/0.4N NaOH was added and the plate was allowed to stand at 37° C.for 1 hour to lyze the cells. The whole content of each well was takenin a vial and neutralized with 1N HCl, and then toluene scintillator(Wako Pure Chemical Ind.) was added to each vial. After stirring, theamount of ³ H-thymidine incorporated in the cells was determined with aliquid scintillation counter. The cellular uptake of ³ H-thymidine wasused as an indicator of cell proliferation. The effect of the drug onthe PDGF-BB (5 ng/ml) uptake of ³ H-thymidine was expressed as %inhibition. The results are shown in Table 8.

                  TABLE 8    ______________________________________    Inhibitory effect on cell proliferation    Compound      Concentration    (Example No.) (M)        % Inhibition    ______________________________________    83 (ii)       3 × 10.sup.-7                             94.9     85 (iii)     3 × 10.sup.-6                             59.2    86 (ii)       1 × 10.sup.-6                             96.6    ______________________________________

The present invention provides a novel tricyclic compound and a saltthereof which have excellent PDGF-inhibiting activity, antihypertensiveactivity, activity of ameliorating renal diseases, and activity oflowering lipid level, and therefore, can be safely used as, therapeuticagents of, for example, hypertension, renal diseases (e.g. acute renalfailure, renal diabetes and nephritis), diseases due toarteriosclerosis, the other cardiovascular diseases, chronic articularrhematism, cancers and hyperlipemia.

The present invention will be explained in more detail by the followingworking examples and reference examples. These are mere examples and arenot intended to restrict the present invention in any manner, and may bemodified within the range of not deviating the scope of this invention.

In Examples and Reference Examples, abbreviations mean as follows.

NMR: Nuclear magnetic resonance spectrum

DMF: dimethylformamide, DMSO: dimethyl sulfoxide, Hz: herz, J: couplingconstant, m: multiplet, q: quartet, t: triplet, d: doublet, s: singlet,b: broad, like: approximate

Room temperature means 10 to 30° C.

EXAMPLE 1 4,5-Dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene·dihydrochloride

i) Synthesis of 5-chloromethylimidazo(1,2-a!pyridine·hydrochloride

To a solution consisting of 58.4 ml (800 mmol) of thionyl chloride and100 ml of methylene chloride was added 23.68 g (160 mmol) of5-hydroxymethylimidazo 1,2-a!pyridine with small portions. The reactionmixture was stirred for one hour at room temperature. Then, the solventand excess amount of thionyl chloride were distilled off under reducedpressure. To the resulting white solid residue was added 100 ml oftoluene. The mixture was shaken sufficiently, then the solvent wasdistilled off under reduced pressure. This process was repeated twice togive 31.85 g (98.0%, white solid) of a crude product.

NMR(200 MHz,D₂ O) δ: 5.09(2H,s), 7.49(1H,t,J=4.8 Hz), 7.85(2H,d,J=4.8Hz), 7.95(1H,d,J=2.4 Hz), 8.16(1H,d,J=2.4 Hz). IR(KBr): 1657, 1543, 1157cm⁻¹.

ii) Synthesis of 5- N-4-(trifluoromethane-sulfonamido)butan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a suspension formed by adding 36.93 g (181.85 mmol) of5-chloromethylimidazo 1,2-a!pyridine hydrochloride to 200 ml ofacetonitrile was added 32.06 g (363.72 mmol) of 1,4-diaminobutane, thenthe mixture was heated for 30 minutes under reflux. After completion ofthe reaction, the reaction mixture was cooled to allow1,4-diaminobutane-dichloride to precipitate, which was collected byfiltration and washed twice with 25 ml of acetonitrile. The filtrate andwashings were combined, to which was added 50.68 ml (363.72 mmol) oftriethylamine. The mixture was stirred sufficiently, to which was added64.97 g (181.85 mmol) of N-phenyltrifluoromethanesulfonimide. Themixture was stirred for two hours at room temperature. After completionof the reaction, the solvent was distilled off under reduced pressure.The residue was extracted with 500 ml of chloroform. The organic layerwas washed with 500 ml of a saturated aqueous saline solution, which wasdried over magnesium sulfate, then the solvent was distilled off underreduced pressure. The residue was purified by silicagel columnchromatography (eluent: chloroform/methanol=20:1) to give 41.60 g(65.3%, a colorless solid) as the desired compound.

NMR(200 MHz,CDCl₃) δ: 1.48(13H,m), 3.24(2H,br), 4.67(2H,br),6.69(1H,d,J=6.2 Hz), 7.19(1H,t,J=6.2 Hz), 7.50-7.80(3H,m). IR(KBr):3320, 1641, 1514, 1367 cm⁻¹.

(iii) Synthesis of 4,5-dihydro-4-4-(trifluoro-methanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene

To a solution of 6.91 g (19.72 mmol) of 5- N-4-(trifluoromethanesulfonamido)butan-1-yl!aminomethyl!-imidazo1,2-a!pyridine in 20 ml of acetic acid was added 22.1 ml (295.8 mmol) ofa 37% aqueous solution of formaldehyde. The mixture was heated at 100°C. for 30 minutes. The solvent was then distilled off under reducedpressure, and the residue was dissolved in 100 ml of a saturated aqueoussolution of potassium hydrogencarbonate. This solution was neutralized,under ice-cooling, with 1N HCl, which was subjected to extracted twicewith 100 ml of chloroform. The organic layer was dried over magnesiumsulfate, then the solvent was distilled off under reduced pressure. Theresidue was purified by silicagel chromatography (eluent:chloroform/methanol=20:1) to give 4.86 g (68.0%, pale yellow liquidproduct).

NMR(200 MHz,CDCl₃) δ: 1.76(4H,m), 2.55(2H,t,J=6.0 Hz), 3.33(2H,t,J=6.0Hz), 3.97(2H,s), 4.00(2H,s), 6.55(1H,d,J=6.8 Hz), 7.10(1H,dd,J=9.2,6.8Hz), 7.25(1H,s), 7.44(1H,d,J=9.2 Hz). IR(neat): 1636, 1483, 1370 cm⁻¹.

iv) Synthesis of 4,5-dihydro-4-4-(trifluoro-methanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

To a solution of 3.21 g (8.87 mmol) of 4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylenein 10 ml of ethanol was added 2.0 ml of 12N HCl. The mixture wassufficiently blended. The solvent was distilled off under reducedpressure to leave 3.86 g of the desired compound (100%, colorlessamorphous).

NMR(200 MHz,DMSO) δ: 1.60(2H,m), 1.85(2H,m), 3.19(4H,m), 4.83(2H,s),4.91(2H,s), 7.54(1H,m), 7.99-8.01(2H,m), 8.20(1H,s), 9.55(1H,t,J=6.0Hz). IR(KBr): 3463, 1662, 1459, 1440, 1373, 1190 cm⁻¹.

EXAMPLE 2 4,5-Dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

i) Synthesis of 5- N-5-(trifluoromethanesulfonamido)-pentan-1-yl!aminomethyl imidazo1,2-a!pyridine

To a suspension of 10.2 g (50.0 mmol) of 5-chloromethylimidazo1,2-a!pyridine hydrochloride in 100 ml of acetonitrile was added 10.2 g(100 mmol) of 1,5-diaminopentane. The mixture was heated for 30 minutesunder reflux. The reaction mixture was cooled to separate1,5-diaminopentane-dihydrochloride as precipitates, which was collectedby filtration and washed 10 ml of acetonitrile twice. The filtrate andthe washing were combined, to which was added 14.0 ml (100 mmol) oftriethylamine. The mixture was stirred sufficiently, to which was added17.86 g (50.0 mmol) of N-phenyltrifluoromethanesulfonimide. The mixturewas stirred for two hours at room temperatures. After completion of thereaction, the solvent was distilled off under reduced pressure. Theresidue was extracted with 250 ml of chloroform. The organic layer waswashed with 200 ml of a saturated aqueous saline solution, dried overmagnesium sulfate, then the solvent was removed under reduced pressure.The residue was purified by means of a silicagel column chromatography(eluent: chloroform/methanol=20:1) to give 12.9 g of the object compound(71.0%, colorless solid substance).

NMR(200 MHz,CDCl₃) δ: 1.45(2H,m), 1.60(4H,m), 2.47(2H,t,J=6.6 Hz),3.28(2H,t,J=6.6 Hz), 4.02(2H,s), 6.78(1H,d,J=7.0 Hz),7.17(1H,dd,J=7.0,9.2 Hz), 7.57(1H,s), 7.58(1H,d,J=9.2 Hz), 7.63(1H,s).IR(KBr): 1637, 1481, 1637, 1295, 1188 cm⁻¹.

ii) Synthesis of 4,5-dihydro-4-5-(trifluoromethane-sulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene

To a solution of 2.52 g (6.91 mmol) of 5- N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl! imidazo1,2-a!pyridine in 8 ml of acetic acid was added 7.8 ml (103.7 mmol) of a37% aqueous solution of formalin. The mixture was heated at 100° C. for30 minutes. The solvent was then distilled off under reduced pressure.The residue was dissolved in 50 ml of a saturated aqueous solution ofpotassium carbonate. This solution was neutralized, under ice-cooling,with 1N HCl, which was extracted twice with 100 ml of chloroform. Theorganic layer was dried over magnesium sulfate, then the solvent wasdistilled off under reduced pressure. The residue was purified bysilicagel column chromatography to give 1.79 g of the desired compound(69.0%, colorless liquid).

NMR(200 MHz,CDCl₃) δ: 1.44(2H,m), 1.60(4H,m), 2.47(2H,t,J=6.6 Hz),3.28(1H,t,J=6.6 Hz), 3.91(2H,s), 4.01(2H,s), 6.53(1H,d,J=6.8 Hz),7.10(1H,dd,J=9.2,6.8 Hz), 7.27(1H,s), 7.39(1H,d,J=9.2 Hz), 8.25(1H,br).IR(neat): 1637, 1522, 1450, 1366, 1221 cm⁻¹.

iii) Synthesis of 4,5-dihydro-4-5-(trifluoromethane-sulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene·dihydrochloride

In a solution consisting of 10 ml of ethanol and 0.5 ml of 12N HCl wasdissolved 0.88 g (2.34 mmol) of 4,5-dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene.The solvent was distilled off under reduced pressure to leave 1.05 g ofthe desired compound (100%, white amorphous).

NMR(200 MHz,DMSO) δ: 1.39(2H,m), 1.55(2H,m), 1.83(2H,m), 3.16(4H,m),4.85(2H,s), 4.93(2H,s), 7.54(1H,m), 8.01(2H,m), 8.19(1H,s),9.40(1H,t,J=5.8Hz). IR(KBr): 3431, 1662, 1549, 1440 cm⁻¹.

EXAMPLE 3 4,5-Dihydro-2-methyl-4- 4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

i) Synthesis of 2-methyl-5-hydroxymethylimidazo 1,2-1!pyridine

To a solution of 8.31 g (40 mmol) of 2-methyl-imidazo1,2-a!pyridine-5-carboxylic acid ethyl ester in 200 ml of methanol wasadded, under ice-cooling, 4.54 g (120 mmol) of sodium borohydride. Themixture was stirred for 3 hours under ice-cooling. The reaction mixturewas poured into 300 ml of ice-water, and the mixture was blendedsufficiently, to which was then added 12N HCl until the pH of thesolution reached 2. This solution was stirred for two hours at roomtemperature, which was then neutralized with a 6N aqueous solution ofsodium hydroxide, followed by distilling off the solvent completelyunder reduced pressure. To the residue was added 300 ml of methanol. Themixture was blended sufficiently, and insolubles were filtered off,followed by distilling off the solvent under reduced pressure to leave5.71 g of a crude product (88%, white solid substance). The crudeproduct was used in the subsequent reaction without purification.

NMR(200 MHz,D₂ O) δ: 2.48(3H,s), 4.83(2H,s), 6.12(1H,br),7.87(1H,d,J=3.0 Hz), 7.71(1H,d,J=3.0 Hz), 7.73(1H,s), 8.01(1H,s).IR(KBr): 3350, 1653, 1643, 1390 cm⁻¹.

ii) Synthesis of 2-methyl-5-chloromethylimidazo1,2-a!pyridine-hydrochloride

To a mixture solution consisting of 12.0 ml (150.0 mmol) of thionylchloride and 25 ml of methylene chloride was added, 4.87 g (30.0 mmol)of 2-methyl-5-hydroxymethylimidazo 1,2-a!pyridine with small portions.The reaction mixture was stirred for one hour at room temperature, thenthe solvent and excess volume of thionyl chloride were distilled offunder reduced pressure to leave a white solid matter. To the solid wasadded 50 ml of toluene, and the mixture was stirred sufficiently,followed by distilling off the solvent under reduced pressure. Thisprocess was repeated twice to give 6.46 g (99.0%, white solid) of acrude product.

NMR(200 MHz,D₂ O) δ: 2.50(3H,s), 5.05(2H,s), 7.44(1H,d,J=2.8 Hz),7.75(1H,s), 7.78(1H,d,J=2.8 Hz), 7.92(1H,s). IR(KBr): 3222, 1657, 1547,1429 cm⁻¹.

iii) Synthesis of 2-methyl-5- N-4-(trifluoro-methanesulfonamido)butan-1-yl!aminomethyl!imidazo1,2-1!pyridine

To a suspension of 6.52 g (30.0 mmol) of 2-methyl-5-chloromethylimidazo1,2-a!pyridine chloride in 60 ml of acetonitrile was added 5.30 g (60.1mmol) of 1,4-diaminobutane. The mixture was heated for 30 minutes underreflux. After completion of the reaction, the reaction mixture wascooled. Precipitates of 1,4-diaminobutane-dihydrochloride then formedwere separated by filtration. The precipitates were washed with 10 ml ofacetonitrile twice. The filtrate and the washings were combined, towhich was added 8.4 ml (60.1 mmol) of triethylamine, and the mixture wasstirred sufficiently. To this solution was added 10.73 g (30.0 mmol) ofN-phenyltrifluoromethanesulfonimide, and the mixture was stirred for twohours at room temperature. After completion of the reaction, the solventwas distilled off under reduced pressure. The residue was extracted with150 ml of chloroform. The organic layer was washed with 150 ml of asaturated aqueous saline solution, which was dried over magnesiumsulfate, followed by distilling off the solvent under reduced pressure.The residue was purified by silicagel column chromatography (eluent:chloroform/methanol=20:1) to give 7.44 g of the desired compound (68.0%,colorless solid).

NMR(200 MHz,CDCl₃) δ: 1.69(4H,m), 2.44(3H,s), 2.74(2H,t,J=6.0 Hz),3.30(2H,t,J=6.0 Hz), 3.97(2H,s), 6.71(1H,d,J=7.0 Hz),7.12(1H,dd,J=7.0,9.0 Hz), 7.35(1H,s), 7.47(1H,d,J=9.0 Hz). IR(KBr):1639, 1483, 1371 cm⁻¹.

iv) Synthesis of 4,5-dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene

In 6 ml of acetic acid was dissolved 2.02 g (5.54 mmol) of 2-methyl-5-N- 4-(trifluoromethanesulfonamido) butan-1-yl!aminomethyl!imidazo1,2-a!pyridine. To the solution was added 6.2 ml (83.15 mmol) of a 37%aqueous solution of formalin, and the mixture was heated for 30 minutesat 100° C. After completion of the reaction, the solvent was distilledoff under reduced pressure. The residue was dissolved in 100 ml of asaturated aqueous solution of potassium carbonate. This solution wasneutralized by the addition of 1N HCl under ice-cooling, which wasextracted twice with 100 ml of chloroform. The extract was dried overmagnesium sulfate, then the solvent was distilled off under reducedpressure. The residue was purified by silica-gel column chromatography(eluent: chloroform/methanol=20:1) to afford 1.45 g of the desiredcompound (72.0%, colorless liquid).

NMR(200 MHz,CDCl₃) δ: 1.73(4H,m), 2.31(3H,s), 2.51(2H,m), 3.31(2H,m),3.94(2H,s), 4.01(2H,s), 6.50(1H,d,J=6.8 Hz), 7.07(1H,dd,J=9.0,6.8 Hz),7.36(1H,d,J=9.0 Hz). IR(neat): 1643, 1506, 1454, 1367 cm⁻¹.

v) Synthesis of 4,5-dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

In a solution consisting of 10 ml of ethanol and 1 ml of 12N HC1 wasdissolved 1.41 g (3.74 mmol) of 4,5-dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene. The solvent was distilledoff under reduced pressure to give the desired compound (100%, whiteamorphous).

NMR(200 MHz,DMSO) δ: 1.60(2H,m), 1.86(2H,m), 2.54(3H,s), 3.40(4H,m),4.84(2H,s), 4.92(2H,s), 7.51(1H,d,J=6.2 Hz), 7.93(2H,m), 9.53(1H,t,J=5.2Hz), IR(KBr): 3428, 1672, 1552, 1450, 1369 cm⁻¹.

EXAMPLE 4 4,5-Dihydro-2-ethyl-4- 5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

i) Synthesis of 2-ethyl-5-hydroxymethylimidazo 1,2-a!pyridine

To a solution of 5.29 g (24.24 mmol) of ethyl ester of 2-ethylimidazo1,2-a!pyridine-5-carboxylic acid was added 2.75 g (72.72 mmol) of sodiumborohydride under ice-cooling. The reaction mixture was stirred for 3hours under ice-cooling. The reaction mixture was then poured into 150ml of ice-water. The reaction mixture was mixed well, to which was added12N HCl until the pH of the solution reached 2. This solution wasstirred for two hours at room temperature, which was neutralized with a6N aqueous solution of sodium hydroxide. The solvent was completelydistilled off under reduced pressure. To the residue was added 200 ml ofmethanol. The mixture was mixed well, then insolubles were filtered off.The solvent was distilled off under reduced pressure to give 2.99 g of acrude product (70%, white solid). This crude product was used, withoutpurification, in the subsequent reaction.

NMR(200 MHz,D₂ O) δ: 1.32(3H,t,J=7.6 Hz), 2.78(2H,q,J=7.6 Hz),4.83(2H,s), 6.15(1H,br), 7.86(1H,d,J=3.0 Hz), 7.74(1H,d,3.0 Hz),7.75(1H,s), 8.00(1H,s). IR(KBr): 3348, 1652, 1644, 1390 cm⁻¹.

ii) Synthesis of 2-ethyl-5-chloromethylimidazo1,2-a!pyridine-hydrochloride

To a mixture solution consisting of 8.8 ml (120.0 mmol) of thionylchloride and 10 ml of methylene chloride was added, 4.23 g (24.0 mmol)of 2-ethyl-5-hydroxymethylimidazo 1,2-a!pyridine with small portions.The reaction mixture was stirred for one hour at room temperature. Then,the solvent and excess volume of thionyl chloride were distilled offunder reduced pressure. To the residual white solid was added 30 ml oftoluene. The mixture was stirred well, and the solvent was distilled offunder reduced pressure. This process repeated twice to give 5.44 g of acrude product (99.0%, white solid), which was used for the subsequentreaction without purification.

NMR(200 MHz,D₂ O) δ: 1.35(3H,t,J=7.6 Hz), 2.85(2H,q,J=7.6 Hz),5.02(2H,s), 7.42(1H,d,J=2.9 Hz), 7.75(1H,s), 7.77(1H,d,J=2.8 Hz),7.90(1H,s). IR(KBr): 3225, 1659, 1550, 1430 cm⁻¹.

iii) Synthesis of 2-ethyl-5- N-5-(trifluoro-methanesulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a suspension of 5.50 g (24.0 mmol) of 2-ethyl-5-chloromethylimidazo1,2-a!pyridine·hydrochloride in 60 ml of acetonitrile was added 4.90 g(48.0 mmol) of 1,5-diaminopentane. The mixture was heated for 30 minutesunder reflux. After completion of the reaction, the reaction mixture wascooled, and then, the resulting precipitate of1.5-diaminopentane·dihydrochloride was separated by filtration and then,washed with 10 ml of acetonitrile twice. The filtrate and the washingswere combined, to which was added 6.7 ml (48.0 mmol) of triethylamine.The mixture was stirred sufficiently. To this solution was added 10.29 g(28.8 mmol) of N-phenyl trifluoromethanesulfonimide, and the mixture wasstirred for two hours at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure. Theresidue was extracted with 150 ml of chloroform. The organic layer waswashed with 150 ml of a saturated aqueous saline solution, which wasdried over magnesium sulfate, followed by distilling off the solventunder reduced pressure. The residue was purified by silicagel columnchromatography (eluent: chloroform/methanol=20:1) to give 6.03 g of thedesired compound (64.0%, colorless solid).

NMR(200 MHz,CDCl₃) δ: 1.33(3H,t,J=7.6 Hz), 1.29-1.63(6H,m),2.64(2H,t,J=6.6 Hz), 2.81(2H,q,J=7.6 Hz), 3.29(2H,t,J=7.0 Hz),3.94(2H,s), 4.85(1H,br,NH), 6.70(1H,d,J=7.0 Hz), 7.11(1H,dd,J=9.0,7.0Hz), 7.39(1H,s), 7.47(1H,d,J=9.0 Hz). IR(KBr): 1645, 1480, 1361 cm⁻¹.

iv) Synthesis of 4,5-dihydro-2-ethyl-4-5-(trifluoro-methanesulfonamido)pentan-1-yl!-3H-1,4,8b-triaza-acenaphthylene

To a solution of 785 mg (2.00 mmol) of 2-ethyl-5- N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine in 5 ml of acetic acid was added 2.25 ml (30.00 mmol) ofa 37% aqueous solution of formalin. The mixture was heated for 30minutes at 100° C. The solvent was then distilled off under reducedpressure. The residue was dissolved in 100 ml of a saturated aqueoussolution of potassium carbonate. This solution was neutralized, underice-cooling, with 1N HCl, which was extracted twice with 100 ml ofchloroform. The organic layer was dried over magnesium sulfate, then thesolvent was distilled off under reduced pressure. The residue waspurified by silicagel column chromatography (eluent:chloroform/methanol=20:1) to give 527 mg of the desired compound (65.2%,colorless liquid).

NMR(200 MHz,CDCl₃) δ: 1.29(3H,t,J=7.6 Hz), 1.43(2H,m), 1.60(4H,m),2.48(2H,t,J=7.0 Hz), 2.72(2H,q,J=7.6 Hz), 3.28(2H,t,J=6.8 Hz),3.91(2H,s), 4.02(2H,s), 6.50(1H,d,J=7.0 Hz), 7.07(1H,dd,J=9.2,7.0 Hz),7.36(1H,d,J=9.2 Hz). IR(neat): 1645, 1508, 1455, 1365 cm⁻¹.

v) Synthesis of 4,5-dihydro-2-ethyl-4-5-(trifluoro-methanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaace-naphthylene-dihydrochloride

In a mixture of 10 ml of ethanol and 1 ml of 12N HCl was dissolved 542mg (1.34 mmol) of4,5-dihydro-2-ethyl-4-(5-trifluoromethanesulfonamidopentan-1-yl)-3H-1,4,8b-triazaacenaphthylene.The solvent was distilled off under reduced pressure to leave 640 mg ofthe desired compound (100%, white amorphous substance).

NMR(200 MHz,DMSO) δ: 1.37(5H,m), 1.57(2H,m), 1.85(2H,m), 2.92(2H,q,J=7.6Hz), 3.15(4H,m), 4.85(2H,s), 4.92(2H,s), 7.68(1H,d,J=6.2 Hz),7.94(2H,m), 9.43(1H,t,J=5.4 Hz). IR(KBr): 3427, 1666, 1550, 1458, 1365cm⁻¹.

EXAMPLE 5 4,5-Dihydro-2-phenyl-4-5-(trifluoromethane-sulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

i) Synthesis of 2-phenyl-5-hydroxymethylimidazo 1,2-a!pyridine

To a solution of 3.14 g (11.79 mmol) of ethyl ester of 2-phenylimidazo1,2-a!pyridine-5-carboxylic acid was added, under ice-cooling, 1.34 g(35.37 mmol) of sodium borohydride. The mixture was stirred for 3 hoursunder ice-cooling. The reaction mixture was poured into 150 ml ofice-water, which was sufficiently blended. To the mixture was added 12NHCl until the pH reached 2. This solution was stirred for two hours atroom temperature, which was neutralized with a 6N aqueous solution ofNaOH. The solvent was then completely distilled off under reducedpressure. To the residue was added 200 ml of methanol. The mixture wassufficiently blended, then insolubles were filtered off. The solvent wasdistilled off under reduced pressure to leave 1.37 g of a crude product(52.0%, white solid). This crude product was used in the subsequentreaction without purification.

NMR(200 MHz,DMSO-d₆) δ: 4.95(2H,s), 6.15(1H,br), 6.90(1H,d,J=6.0 Hz),7.21-7.54(6H,m), 8.03(1H,d,J=7.0 Hz), 8.45(1H,s). IR(KBr): 3360, 1663,1653, 1395 cm⁻¹.

ii) Synthesis of 2-phenyl-5-chloromethylimidazo1,2-a!pyridine·hydrochloride

To a mixture solution consisting of 3.7 ml (50.0 mmol) of thionylchloride and 5.0 ml of methylene chloride was added, 2.24 g (10.0 mmol)of 2-phenyl-5-hydroxymethylimidazo 1,2-a!pyridine with small portion.The reaction mixture was stirred for one hour at room temperature, thenthe solvent and excess volume of thionyl chloride were distilled offunder reduced pressure to leave a white solid. Toluene (20 ml) was addedto the white solid, and the mixture was sufficiently blended, followedby distilling off the solvent under reduced pressure. This process wasrepeated twice to give 2.76 g a crude product (99.0%, white solid).

NMR(200 MHz,DMSO-d₆) δ: 5.10(2H,s), 6.95(1H,d,J=6.0 Hz),7.25-7.60(6H,m), 8.09(1H,d,J=7.0 Hz), 8.51(1H,s). IR(KBr): 3222, 1665,1546, 1431 cm⁻¹.

iii) Synthesis of 2-phenyl-5- N-5-(trifluoromethane-sulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a suspension of 2.79 g (10.0 mmol) of 2-phenyl-5-chloromethylimidazo1,2-a!pyridine·hydrochloride in 35 ml of acetonitrile was added 2.04 g(20.0 mmol) of 1,5-diaminopentane. The mixture was heated for 30 minutesunder reflux. After completion of the reaction, the reaction mixture wascooled. The resulting precipitate of 1,5-diaminopentane-dihydrochloridewas separated by filtration and washed twice with 10 ml of acetonitrile.The filtrate and washings were combined, to which was added 2.8 ml (20.0mmol) of triethylamine. The mixture was stirred sufficiently, to whichwas added 4.29 g (12.0 mmol) of N-phenyltrifluoromethanesulfonimide, andthe mixture was stirred for two hours at room temperature. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure. The residue was subjected to extraction with 100 ml ofchloroform. The organic layer was washed with 100 ml of a saturatedaqueous saline solution and dried over magnesium sulfate. Then, thesolvent was distilled off under reduced pressure. The residue waspurified by silicagel column chromatography (eluent:chloroform/methanol=20:1) to give 2.66 g of the desired compound (60.3%,colorless solid).

NMR(200 MHz,DMSO-d₆) δ: 1.51(6H,m), 2.62(2H,t,J=6.8 Hz), 3.12(2H,t,J=6.8Hz), 4.07(2H,s), 6.91(1H,d,J=6.0 Hz), 7.21-7.54(6H,m), 8.02(1H,d,J=1.0Hz), 8.42(1H,s). IR(KBr): 1640, 1480, 1370 cm⁻¹.

iv) Synthesis of 4,5-dihydro-2-phenyl-4-5-(trifluoro-methanesulfonamido)pentan-1-yl!-3H-1,4,8b-triaza-acenaphthylene

To a solution of 440 mg (1.00 mmol) of 2-phenyl-5- N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-1!pyridine in 5 ml of acetic acid was added 1.12 ml (15.00 mmol) ofa 37% aqueous solution of formalin. The mixture was heated for 30minutes at 100° C. After completion of the reaction, the solvent wasdistilled off under reduced pressure. The residue was dissolved in 100ml of a saturated aqueous solution of potassium carbonate. This solutionwas neutralized, under ice-cooling, with 1N HCl, which was extractedtwice with 100 ml of chloroform. The organic layer was dried overmagnesium sulfate, then the solvent was distilled off under reducedpressure. The residue was purified by silicagel column chromatography(eluent: chloroform/methanol=20:1) to give 354 mg of the object compound(78.3%, colorless liquid).

NMR(200 MHz,CDCl₃) δ: 1.24(2H,m), 1.44(4H,m), 2.39(2H,t,J=7.0 Hz),3.14(2H,t,J=7.0 Hz), 3.90(2H,s), 4.21(2H,s), 6.52(1H,d,J=6.8 Hz),7.12(1H,dd,J=9.2,6.8 Hz), 7.33(1H,d,J=7.2 Hz), 7.40-7.72(5H,m).IR(neat): 1645, 1508, 1455, 1366 cm⁻¹.

v) Synthesis of 4,5-dihydro-2-phenyl-4-5-(trifluoro-methanesulfonamido)pentan-1-yl!-3H-1,4,8b-triaza-acenaphthylene·dihydrochloride

In a solution consisting of 5 ml of ethanol and 0.1 ml of 12N HCl wasdissolved 254 mg (0.56 mmol) of 4,5-dihydro-2-phenyl-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene.The solvent was distilled under reduced pressure to give 295 mg of thedesired compound (100%, white amorphous).

NMR(200 MHz,DMSO-d₆) δ: 1.48(2H,m), 1.59(2H,m), 1.85(2H,m), 3.16(4H,m),4.87(2H,s), 4.98(2H,s), 7.45(1H,t,J=3.6 Hz), 7.61-7.70(3H,s),7.84-7.94(4H,m), 9.38(1H,t,J=5.8 Hz). IR(KBr): 3423, 1662, 1441, 1369,1192 cm⁻¹.

EXAMPLE 6 4,5-Dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

i) Synthesis of 5- N-tert-butoxycarbonyl-N-4-trifluoromethanesulfonamido)butan-1-yl!aminomethyl!-imidazo1,2-a!pyridine

To a solution of 29.10 g (83.05 mmol) of 5- N-4-(trifluoromethanesulfonamido)butan-1-yl!aminomethyl! imidazo1,2-a!pyridine in 100 ml of ethanol was added dropwise, taking 10minute, 18.13 g (83.13 mmol) of di-tert-butyl dicarbonate. The reactionmixture was stirred for one hour at room temperature, then the solventwas distilled off under reduced pressure. The residue was purified bysilicagel column chromatography (eluent: chloroform/methanol=20:1) togive 26.33 g of the desired compound(70.4%, pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.48(13H,m), 3.24(4H,br), 4.67(2H,br),6.69(1H,d,J=6.2 Hz), 7.19(1H,t,J=6.2 Hz), 7.50-7.80(3H,m). IR(KBr):2978, 1691, 1516, 1379, 1228 cm⁻¹.

ii) Synthesis of 3-trichloroacetyl-5- N-tert-butoxy-carbonyl-N-4-(trifluoromethanesulfonamido)butan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a solution of 7.86 g (17.44 mmol) of 5- N-tert-butoxycarbonyl-N-4-(trifluoromethanesulfonamido)butan-1-yl!aminomethyl!imidazo1,2-a!pyridine and 6.39 g (52.31 mmol) of 4-dimethylaminopyridine in 100ml of chloroform was added dropwise, taking 5 minutes, 5.84 ml (52.31mmol) of trichloroacetyl chloride. The reaction mixture was heated for16 hours under reflux. The reaction mixture was poured into ice-water,which was neutralized with a saturated aqueous solution of sodiumhydrogencarbonate, followed by extraction with 100 ml of chloroform. Theorganic layer was washed with 200 ml of a saturated aqueous salinesolution and dried over magnesium sulfate, then the solvent wasdistilled off under reduced pressure. The residue was purified bysilicagel column chromatography (eluent: chloroform/methanol=100:1) togive 5.72 g of the desired compound (55.0%, pale yellow liquid).

NMR(200 MHz,CDCl₃) δ: 1.55-1.85(4H,m), 3.38(2H,t,J=7.4 Hz),3.77(2H,t,J=6.6 Hz), 4.50(2H,s), 7.11(1H,d,J=6.6 Hz),7.69(1H,dd,J=8.6,7.2 Hz), 7.81(1H,d,J=8.6 Hz), 8.95(1H,s). IR(neat):2978, 1755, 1705, 1768, 1404 cm⁻¹.

iii) Synthesis of 4,5-dihydro-4-4-(trifluoro-methanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one

To a solution of 5.25 g (8.81 mmol) of 3-trichloroacetyl-5-N-tert-butoxycarbonyl-N-4-(trifluoromethanesulfonamido)butan-1-yl!aminomethyl!imidazo1,2-a!pyridine in 25 ml of chloroform was added dropwise 2.5 ml (17.62mmol) of iodotrimethylsilane at room temperature. The reaction mixturewas stirred for 10 minutes, which was poured into ice-water, followed byneutralization with a saturated aqueous solution of sodiumhydrogencarbonate. This solution was extracted with 250 ml of ethylacetate. The organic layer was washed with 100 ml of a 1.0N aqueoussolution of sodium thiosulfate, then with 100 ml of a saturated aqueoussaline solution. The organic layer was dried over magnesium sulfate,then the solvent was distilled off under reduced pressure. The residuewas purified by silicagel column chromatography (eluent:chloroform/methanol=20:1) to give 2.16 g (65.0%) of the desiredcompound.

NMR(200 MHz,CDCl₃) δ: 1.41-1.88(4H,m), 3.42(2H,t,J=6.0 Hz),3.64(2H,t,J=6.6 Hz), 5.02(2H,s), 6.77(1H,d,J=7.0 Hz),7.35(1H,dd,J=9.2,7.0 Hz), 7.54(1H,d,J=9.2 Hz), 8.15(1H,s). IR(KBr):1641, 1542, 1369, 1189 cm⁻¹.

iv) Synthesis of 4,5-dihydro-4-4-(trifluoromethane-sulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

In a mixture of 50 ml of ethanol and 1 ml of 12N HCl was dissolved 2.87g (7.63 mmol) of 4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one,and the solvent was distilled off under reduced pressure to leave 3.15 gof the desired compound (100%, pale yellow solid matter).

NMR(200 MHz,DMSO) δ: 1.45-1.78(4H,m), 3.20(2H,dd,J=9.6,5.6 Hz),3.55(2H,t,J=6.6 Hz), 5.25(2H,s), 7.43(1H,d,J=8.0 Hz), 7.85(1H,d,J=8.2Hz), 7.99(1H,dd,J=8.2,8.0 Hz), 8.63(1H,s), 9.44(1H,t,J=5.6 Hz). IR(KBr):1649, 1560, 1479, 1369 cm⁻¹.

EXAMPLE 7 4,5-Dihydro-4-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

i) Synthesis of 5- N-3-(trifluoromethane-sulfonamido)propan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a suspension of 6.89 g (33.9 mmol) of 5-chloromethylimidazo1,2-a!pyridine hydrochloride in 100 ml of acetonitrile was added 5.03 g(67.9 mmol) of 1,3-diaminopropane. The mixture was heated for 30 minutesunder reflux. After completion of the reaction, the reaction mixture wascooled to cause precipitation of 1,3-diaminopropane·dihydrochloride. Theprecipitate was separated by filtration and washed twice with 10 ml ofacetonitrile. The filtrate and the washings were combined, to which wasadded 9.46 ml (67.9 mmol) of triethylamine, and the mixture was stirredsufficiently. To the solution was added 24.26 g (67.9 mmol) ofN-phenyltrifluoromethanesulfonimide, and the mixture was stirred for twohours at room temperature. After completion of the reaction, the solventwas distilled off under reduced pressure. The residue was extracted with250 ml of chloroform. The organic layer was washed with 200 ml of asaturated aqueous saline solution, which was dried over magnesiumsulfate, followed by distilling off the solvent under reduced pressure.The residue was purified by silicagel column chromatography (eluent:chloroform/methanol=20:1) to give 7.18 g of the desired compound (63.0%,colorless solid matter).

NMR(200 MHz,CDCl₃) δ: 1.82(2H,m), 2.88(2H,t,J=5.8 Hz), 3.43(2H,t,J=5.8Hz), 4.00(2H,s), 4.85(1H,br), 6.73(1H,d,J=6.6 Hz), 7.12(1H,dd,J=9.2,6.6Hz), 7.54(1H,d,J=9.2 Hz), 7.57(2H,s). IR(KBr): 1620, 1464, 1367, 1225,1184 cm⁻¹.

ii) Synthesis of 5- N-tert-butoxycarbonyl-N-3-(trifluoromethanesulfonamido)propan-1-yl!-aminomethyl!imidazo1,2-a!pyridine

To a solution of 3.03 g (9.01 mmol) of 5- N-3-(trifluoromethanesulfonamido)propan-1-yl!aminomethyl! imidazo1,2-a!pyridine in 20 ml of ethanol was added dropwise, taking 5 minutes,1.97 g (9.01 mmol) of di-tert-butyl dicarbonate. The reaction mixturewas stirred for one hour at room temperature, then the solvent wasdistilled off under reduced pressure. The residue was purified by meansof a silicagel column chromatography (eluent: chloroform/methanol=20:1)to give 3.38 g of the desired compound (86.1%, colorless liquid).

NMR(200 MHz,CDCl₃) δ: 1.51(9H,s), 1.60(2H,m), 3.21(2H,t,J=6.2 Hz),3.41(2H,br), 4.66(2H,s), 6.88(1H,d,J=7.0 Hz), 7.18(1H,m), 7.53(3H,m).IR(KBr): 1691, 1469, 1416, 1371, 1186 cm⁻¹.

iii) Synthesis of 3-trichloroacetyl-5- N-tert-butoxy-carbonyl-N-3-(trifluoromethanesulfonamido)propan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a solution of 3.15 g (7.22 mmol) of 5- N-tert-butoxycarbonyl-N-3-(trifluoromethanesulfon-amido)propan-1-yl!aminomethyl!imidazo1,2-a!pyridine and 2.65 g (21.65 mmol) of 4-dimethylaminopyridine in 30ml of chloroform was added dropwise, while stirring at room temperaturefor 3 minutes, 2.4 ml (21.65 mmol) of trichloroacetyl chloride. Thereaction mixture was heated for 15 hours under reflux. After completionof the reaction, the reaction mixture was poured into ice-water, whichwas neutralized with a saturated aqueous solution of sodiumhydrogencarbonate. The solution was extracted with 150 ml of chloroform.The organic layer was washed with 250 ml of a saturated aqueous salinesolution and dried over magnesium sulfate. The solvent was thendistilled off under reduced pressure. The residue was purified bysilicagel column chromatography (eluent: chloroform/methanol=100:1) togive 2.31 g of the desired compound (54.8%, pale yellow liquid).

NMR(200 MHz,CDCl₃) δ: 1.21(9H,s), 1.84(2H,m), 3.35(2H,m),3.53(2H,t,J=5.8 Hz), 4.46(2H,s), 7.09(1H,d,J=7.2 Hz),7.73(1H,dd,J=8.8,7.4 Hz), 7.85(1H,dd,J=7.6 Hz), 8.98(1H,s). IR(KBr):1680, 1471, 1373, 1296, 1188 cm⁻¹.

iv) Synthesis of 4,5-dihydro-43-(trifluoromethane-sulfonamido)propan-1-yl!-3H-1,4,8b-triaza-acenaphthylene-3-one

To a solution of 1.16 g (2.00 mmol) of 3-trichloroacetyl-5-N-tert-butoxycarbonyl-N-3-(trifluoromethanesulfonamido)propan-1-yl!aminomethyl!imidazo1,2-a!pyridine in 25 ml of chloroform was added dropwise 0.57 ml (4.00mmol) of iodotrimethylsilane at room temperature. The reaction mixturewas stirred for 15 minutes, which was then poured into ice-water,followed by neutralization with a saturated aqueous solution of sodiumhydrogencarbonate. This solution was extractedith 150 ml of ethylacetate. The organic layer was washed with 100 ml of a 1.0N aqueoussolution of sodium thiosulfate, then with 100 ml of a saturated aqueoussaline solution. The organic layer was dried over magnesium sulfate,followed by distilling off the solvent under reduced pressure. Theresidue was purified by silicagel column chromatography (eluent:chloroform/methanol=20:1) to give 397 mg of the desired compound (54.8%,pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.95(2H,m), 3.34(2H,t,J=5.8 Hz), 3.73(2H,t,J=6.0Hz), 5.04(2H,s), 6.79(1H,d,J=7.0 Hz), 7.68(1H,br,NH), 8.13(1H,s).IR(KBr): 1637, 1545, 1367, 1184 cm⁻¹.

v) Synthesis of 4,5-dihydro-4-3-(trifluoromethane-sulfonamido)propan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3-one-hydrochloride

In a mixture solution consisting of 5 ml of ethanol and 0.1 ml of 12NHCl was dissolved 145 mg (0.40 mmol) of 4,5-dihydro-4-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8bbtriazaacenaphthylen-3-one.The solvent was distilled off under reduced pressure to leave 160 mg ofthe desired compound (100%, pale yellow solid substance).

NMR(200 MHz,DMSO) δ: 1.91(2H,m), 3.26(2H,q,J=6.0 Hz), 3.60(2H,t,J=7.6Hz), 5.28(2H,s), 7.46(1H,d,J=6.8 Hz), 7.88(1H,d,J=8.8 Hz),8.02(1H,dd,J=8.8,6.8 Hz), 8.66(1H,s), 9.52(1H,t,J=5.8 Hz). IR(KBr):3455, 1659, 1444, 1371, 1182 cm⁻¹.

EXAMPLE 8 4,5-Dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

i) Synthesis of 5- N-tert-butoxycarbonyl-N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl!-imidazo1,2-a!pyridine

To a solution of 5.00 g (13.72 mmol) of 5- N-5-(trifluoromethanesulfonamido)pentan-1-yl)aminomethyl!imidazo1,2-a!pyridine in 25 ml of ethanol was added dropwise, taking 5 minutes,2.99 g (13.72 mmol) of di-tert-butyl dicarbonate. The reaction mixturewas stirred for one hour at room temperature, then the solvent wasdistilled off under reduced pressure. The residue was purified bysilicagel column chromatography (eluent: chloroform/methanol=20:1) togive 5.73 g of the desired compound (90.2%, colorless liquid).

NMR(200 MHz,CDCl₃) δ: 1.28(6H,m), 1.48(9H,s), 3.10-3.25(4H,m),4.68(2H,s), 6.68(1H,d,J=6.8 Hz), 7.19(1H,t,J=6.8 Hz), 7.57(1H,s),7.61(1H,s), 7.75(1H,br). IR(neat): 1699, 1512, 1471, 1419 cm⁻¹.

ii) Synthesis of 3-trichloroacetyl-5- N-tert-butoxy-carbonyl-N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a solution of 3.55 g (7.64 mmol) of 5- N-tert-butoxycarbonyl-N-5-(trifluoromethane-sulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine and 2.80 g (22.92 mmol) of 4-dimethylaminopyridine in 35ml of chloroform was added dropwise 2.6 ml (22.92 mmol) oftrichloroacetyl chloride, while stirring at room temperature for 3minutes. The reaction mixture was heated for 15 hours under reflux. Thereaction mixture was poured into ice-water, which was neutralized with asaturated aqueous solution of sodium hydrogencarbonate, which wasextracted with 150 ml of chloroform. The organic layer was washed with250 ml of a saturated aqueous saline solution, which was dried overmagnesium sulfate, followed by distilling off the solvent under reducedpressure. The residue was purified by silicagel column chromatography(eluent: chloroform/methanol=100:l) to give 2.70 g of the desiredcompound (58.2%, pale yellow liquid).

NMR(200 MHz,CDCl₃) δ: 1.23(9H,s), 1.48(2H,m), 1.69(4H,m), 3.35(4H,m),4.49(2H,s), 6.31(1H,br), 7.13(1H,d,J=7.0 Hz), 7.72(1H,dd,J=8.8,7.0 Hz),7.84(1H,d,J=8.8 Hz), 8.96(1H,s). IR(neat): 1695, 1670, 1497, 1470 cm⁻¹.

iii) Synthesis of 4,5-dihydro-4-5-(trifluoro-methanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3-one

To a solution of 1.75 g (2.87 mmol) of 3-trichloroacetyl-5-N-tert-butoxycarbonyl-N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine in 25 ml of chloroform was added dropwise 0.82 ml (5.74mmol) of iodotrimethylsilane at room temperature. The reaction mixturewas stirred for 15 minutes, which was poured into ice-water, followed byneutralization with a saturated aqueous solution of sodiumhydrogencarbonate. This solution was extracted with 150 ml of ethylacetate. The organic layer was washed with a 1.0N aqueous solution ofsodium thiosulfate, then with 100 ml of a saturated aqueous salinesolution. The organic layer was dried over magnesium sulfate, followedby distilling off the solvent under reduced pressure. The residue waspurified by silicagel column chromatography (eluent:chloroform/methanol=20:1) to give 706 mg of the object product (63.1%,pale yellow solid substance).

NMR(200 MHz,CDCl₃) δ: 1.48(2H,m), 1.71(4H,m), 3.32(2H,t,J=6.6 Hz),3.57(2H,t,J=6.8 Hz), 4.99(2H,s), 6.74(1H,d,J=7.0 Hz),7.30(1H,dd,J=9.2,7.0 Hz), 7.48(1H,d,J=9.2Hz), 8.07(1H,s), 8.11(1H,br).IR(KBr): 1707, 1610, 1544, 1332, 1219 cm⁻¹.

iv) Synthesis of 4,5-dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one·hydrochloride

In a mixture solvent consisting of 5 ml of ethanol and 0.1 ml of 12N HClwas dissolved 593 mg (1.52 mmol) of 4,5-dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazacenaphthylen-3-one.The solvent was distilled off under reduced pressure to leave 650 mg ofthe desired compound (100%, pale yellow solid).

NMR(200 MHz,DMSO) δ: 1.40(2H,m), 1.60(4H,m), 3.15(4H,m), 5.27(2H,s),1.47(1H,d,J=7.2 Hz), 7.55(1H,d,J=9.0 Hz), 8.03(1H,dd,J=9.0,7.2 Hz),8.64(1H,s), 9.45(1H,t,J=5.4 Hz). IR(KBr): 1720, 1655, 1442, 1365, 1188cm⁻¹.

EXAMPLE 9 4,5-Dihydro-2-methyl-4- 4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4, 8b-triazaacenaphthylen-3-one-hydrochloride

i) Synthesis of 2-methyl-5- N-tert-butoxycarbonyl-N-4-(trifluoromethanesulfonamido)butan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a solution of 2.41 g (6.61 mmol) of 2-methyl-5- N-4-(trifluoromethanesulfonamido)butan-1-yl!aminomethyl!imidazo1,2-a!pyridine in 15 ml of ethanol was added dropwise, for 5 minutes,1.44 g (6.61 mmol of di-tert-butyl dicarbonate. The reaction mixture wasstirred for one hour at room temperature, then the solvent was distilledoff under reduced pressure. The residue was purified by silicagel columnchromatography (eluent: chloroform/methanol=20:1) to give 2.21 g of thedesired compound (72.1%, colorless liquid).

NMR(200 MHz,CDCl₃) δ: 1.49(9H,s), 2.44(3H,s), 3.23(4H,m), 4.62(2H,s),6.61(1H,d,J=6.8 Hz), 7.14(1H,t,J=8.6 Hz), 7.35(1H,br), 7.48(1H,d,J=8.6Hz). IR(neat): 1686, 1510, 1467, 1367 cm⁻¹.

ii) Synthesis of 2-methyl-3-trichloroacetyl-5- N-tert-butoxycarbonyl-N-4-(trifluoromethanesulfonamido)butan-1-yl)aminomethyl!imidazo1,2-a!pyridine

To a solution of 2.90 g (6.24 mmol) of 2-methyl-5-N-tert-butoxycarbonyl-N-4-(trifluoromethane-sulfonamido)butan-1-yl!aminomethyl!imidazo1,2-a!pyridine and 2.29 g (18.73 mmol) of 4-dimethylaminopyridine in 25ml of chloroform was added dropwise, for 3 minutes, 2.1 ml (18.73 mmol)of trichloroacetyl chloride. The reaction mixture was heated for 20hours under reflux. The reaction mixture was then poured into ice-water,which was neutralized with a saturated aqueous solution of sodiumhydrogencarbonate, followed by extraction with 100 ml of chloroform. Theorganic layer was washed with 200 ml of a saturated aqueous salinesolution and dried over magnesium sulfate, followed by distilling offthe solvent under reduced pressure. The residue was purified bysilicagel column chromatography (eluent: chloroform/methanol=100:1) togive 2.47 g of the desired compound (65.2%, pale yellow liquid).

NMR(200 MHz,CDCl₃) δ: 1.23(9H,br), 1.66(4H,m), 2.83(3H,s), 3.38(4H,m),4.07(2H,s), 6.96(1H,d,J=7.0 Hz), 7.60(1H,dd,J=8.8,7.0 Hz),7.75(1H,d,J=8.8 Hz). IR(neat): 1693, 1672, 1465, 1365 cm⁻¹.

iii) Synthesis of 4,5-dihydro-2-methyl-4-4-(trifluoro-methanesulfonamido)-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one

To a solution of 781 mg (1.28 mmol) of 2-methyl-3-trichloroacetyl-5-N-tert-butoxycarbonyl-N- 4-(trifluoromethanesulfonamido)butan-1-yl)aminomethyl!imidazo 1,2-a!pyridine in 10 ml of chloroform wasadded dropwise, at room temperature, 0.36 ml (2.56 mmol) ofiodotrimethylsilane. The reaction mixture was stirred for 10 minutes,which was poured into ice-water, followed by neutralization with asaturated aqueous solution of sodium hydrogencarbonate. This solutionwas extracted with 100 ml of ethyl acetate. The organic layer was washedwith 50 ml of a 1.0N aqueous solution of sodium thiosulfate, then with50 ml of a saturated aqueous saline solution. The organic layer wasdried over magnesium sulfate, then the solvent was distilled off underreduced pressure. The residue was purified by silicagel columnchromatography (eluent: chloroform/methanol=20:1) to give 290 mg of thedesired compound (58.0%, pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.86(4H,m), 2.73(3H,s), 3.61(4H,m), 4.97(2H,s),6.68(1H,d,J=6.8 Hz), 7.28(1H,dd,J=9.2,6.8 Hz), 7.41(1H,d,J=9.2 Hz).IR(KBr): 1697, 1660, 1535, 1448 cm⁻¹.

iv) Synthesis of4,5-dihydro-2-methyl-4-(4-trifluoro-methanesulfonamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

234 mg (0.6 mmol) of 4,5-dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onewas dissolved in a mixture solvent consisting of 2 ml of ethanol and0.05 ml of 12N HCl. The solvent was distilled off under reduced pressureto leave 256 mg of the desired compound (100%, pale yellow solidsubstance).

NMR(200 MHz,CDCl₃) δ: 1.65(2H,m), 1.81(2H,m), 2.56(3H,s), 3.15(4H,m),5.27(1H,s), 7.47(1H,d,J=7.2 Hz), 7.87(1H,d,J=9.0 Hz),8.03(1H,dd,J=9.0,7.2 Hz), 8.67(1H,s), 9.31(1H,br). IR(KBr): 3428, 1716,1664, 1444 cm⁻¹.

EXAMPLE 10 4,5-Dihydro-2-ethyl-4-5-(trifluoromethanesulfonamido)-pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-hydrochloride

i) Synthesis of 2-ethyl-5-tert-butoxycarbonyl-N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl!-imidazo1,2-a!pyridine

To a solution of 3.00 g (7.64 mmol) of 2-ethyl-5- N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine in 20 ml of ethanol was added dropwise, for 5 minutes,1.67 g (7.64 mmol) of di-tert-butyl dicarbonate. The mixture was stirredfor one hour at room temperature, then the solvent was distilled offunder reduced pressure. The residue was purified by silicagel columnchromatography (eluent: chloroform/methanol=20:1) to give 3.09 g of thedesired compound (82.1%, colorless liquid).

NMR(200 MHz,CDCl₃) δ: 1.21-1.45(9H,m), 1.49(9H,s), 2.82(2H,q,J=7.6 Hz),3.06(2H,br), 3.22(2H,br), 4.65(2H,br), 6.60(1H,d,J=6.0 Hz), 7.13(2H,m),7.51(1H,d,J=9.2 Hz). IR(neat): 1684, 1512, 1462, 1365 cm⁻¹.

ii) Synthesis of 2-ethyl-3-trichloroacetyl-5- N-tert-butoxycarbonyl-N-5-(trifluoromethanesulfonamido)-pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine

To a solution of 2.85 g (5.79 mmol) of 2-methyl-5-N-tert-butoxycarbonyl-N-5-(trifluoromethane-sulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine and 3.53 g (28.93 mmol) of 4-dimethylaminopyridine in 35ml of chloroform was added dropwise, for 3 minutes under stirring atroom temperature, 3.2 ml (28.93 mmol) of trichloroacetyl chloride. Thereaction mixture was heated for 20 hours under reflux. After completionof the reaction, the reaction mixture was poured into ice-water, whichwas neutralized with a saturated aqueous solution of sodiumhydrogencarbonate, followed by extraction with 100 ml of chloroform. Theorganic layer was washed with 200 ml of a saturated aqueous salinesolution, which was dried over magnesium sulfate, followed by distillingoff the solvent under reduced pressure. The residue was purified bysilicagel column chromatography (eluent: chloroform/methanol=100:1) togive 2.04 g of the desired compound (55.2%, pale yellow liquid).

NMR(200 MHZ,CDCl₃) 8: 1.23(9H,br), 1.43(3H,t, J=7.6 Hz), 1.65(6H,m),3.15(2H,q,J=7.6 Hz), 3.34(4H,m), 4.11(2H,s), 6.94(1H,d,J=7.0 Hz),7.57(1H,dd,J=8.8,7.0 Hz), 7.71(lH,d,J=8.8Hz). IR(neat): 1690, 1670,1470, 1363 cm⁻¹.

iii) Synthesis of 4,5-dihydro-2-ethyl-4-5-(trifluoro-methanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one

To a solution of 1.73 g (2.71 mmol) of 2-ethyl-3-trichloroacetyl-5-N-tert-butoxycarbonyl-N-5-(trifluoromethanesulfonamido)pentan-1-yl!aminomethyl!imidazo1,2-a!pyridine in 15 ml of chloroform was added dropwise 0.80 ml (5.42mmol) of iodotrimethylsilane at room temperature. The reaction mixturewas stirred for 10 minutes, which was poured into ice-water, followed byneutralization with a saturated aqueous solution of sodiumhydrogencarbonate. This solution was extracted with 100 ml of ethylacetate. The organic layer was washed with 50 ml of 1.0N aqueoussolution of sodium thiosulfate, then with 50 ml of a saturated aqueoussaline solution. The organic layer was dried over magnesium sulfate,then the solvent was distilled off under reduced pressure. The residuewas purified by silicagel column chromatography (eluent:chloroform/methanol=20:1) to give 603 mg of the desired compound (52.3%,pale yellow solid).

NMR(200 MHZ,CDCl₃) δ: 1.35(3H,t,J=7.6 Hz), 1.48(2H,m), 1.70(4H,m),3.13(2H,q,J=7.6 Hz), 3.33(2H,t,J=6.2 Hz), 3.58(2H,t,J=6.6 Hz),4.96(2H,s), 6.68(1H,d,J=7.0 Hz), 7.00(1H,br), 7.28(1H,dd,J=8.8,7.0 Hz),7.44(1H,d,J=8.8 Hz). IR(KBr): 1700, 1650, 1537, 1446 cm⁻¹.

iv) Synthesis of 4,5-dihydro-2-ethyl-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

In a mixture solvent consisting of 2 ml of ethanol and 0.05 ml of 12NHCl was dissolved 110 mg (0.26 mmol) of 4,5-dihydro-2-ethyl-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one.The solvent was distilled off under reduced pressure to leave 120 mg ofthe desired compound (100%, pale yellow solid).

NMR(200MHz,DMSO) δ: 1.18(3H,t,J=7.6 Hz), 1.32(2H,m), 1.53(4H,m),3.01(t,2H,J=6.2 Hz), 3.42(2H,t,J=6.6 Hz), 5.26(2H,s), 7.45(1H,d,J=7.2Hz), 7.86(1H,d,J=9.0 Hz), 8.01(1H,dd,J=9.0,7.2 Hz), 8.65(1H,s),9.32(1H,br). IR(KBr): 3425, 1720, 1665, 1442 cm⁻¹.

EXAMPLE 11 4,5-Dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4,5-dihydro-4-4-(trifluoromthane-sulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 5.05 g (57.3 mmol) of 1,4-diaminobutane and 14.81 g(114.6 mmol) of N,N-diisopropylethylamine in 200 ml of acetonitrile wasadded a solution of 19.22 g (57.3 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine in 100 ml ofacetonitrile. The mixture was heated for 0.5 hour under reflux. Thereaction mixture was left standing for cooling. Insolubles were thenfiltered off. To the filtrate was added 24.56 g (68.7 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was stirred for 0.5hour at room temperature. The solvent was distilled off. To the residuewas added chloroform, and the mixture was washed with an aqueoussolution of sodium hydrogencarbonate, which was dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified by means of a column chromatography (eluent: ethyl acetate).The purified product was recrystallized from ethyl acetate. Thecrystalline product was collected by filtration, washed with ethylacetate and dried to give 9.06 g of the desired compound (40.5%,colorless crystals), m.p.205.0-207.0° C.

Elemental Analysis for C₁₄ H₁₃ N₄ O₄ SF₃ : Calcd.: C, 43.08; H, 3.36; N,14.35. Found: C, 43.32; H, 3.43; N, 14.30. NMR(200 MHz,CDCl₃ -DMSO-d₆)δ: 1.60-1.92(4H,m), 3.26(2H,t,J=6.6 Hz), 4.19(2H,t,J=7.0 Hz),7.83(1H,dd,J=8.8,7.6 Hz), 8.18(1H,d,J=7.6 Hz), 8.20(1H,d,J=8.8 Hz),8.60(1H,br), 8.62(1H,s).

ii) Synthesis of 4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione·hydrochloride

To a suspension of 204 mg (0.52 mmol) of 4,5-dihydro-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazacenaphthylene-3,5-dionein 10 ml of methanol was added 0.12 ml of conc. HCl, then the solventwas distilled off. To the residue was added acetone, and the resultingsolid substance was washed with acetone and dried to give 170 mg of thedesired compound (76.2%, colorless solid substance), m.p.206.0-207.0° C.

Elemental Analysis for C₁₄ H₁₃ N₄ O₄ SF₃ ·HCl: Calcd.: C, 39.40; H,3.31; N, 13.13. Found: C, 39.42; H, 3.38; N, 12.95. NMR(200 MHz,DMSO-d₆)δ: 1.50-1.80(4H,m), 3.18(2H,m), 4.04(2H,t,J=6.6 Hz),7.92(1H,dd,J=8.8,7.4 Hz), 8.14(1H,dd,J=7.4,1.0 Hz), 8.31(1H,dd,J=8.8,1.0Hz), 8.69(1H,s), 9.35(1H,br).

EXAMPLE 12 4,5-Dihydro-4-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4,5-dihydro-4-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 273 mg (3.68 mmol) of 1,3-diaminopropane and 951 mg(7.36 mmol) of N,N-diisopropylethylamine in 15 ml of acetonitrile wasadded a solution of 1.235 g (3.68 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine in 15 ml ofacetonitrile. The mixture was heated for 45 minutes under reflux. Aftercooling, the resulting insolubles were filtered off. To the filtrate wasadded 1.578 g (4.42 mmol) of N-phenyltrifluoromethanesulfonimide. Themixture was stirred for one hour at room temperature. The solvent wasdistilled off. To the residue was added chloroform. The mixture waswashed with an aqueous solution of sodium hydrogencarbonate, dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by column chromatography (eluent: ethyl acetate),which was crystallized from ethyl acetate. The crystalline product wascollected by filtration, washed with ether, and dried to give 607 mg ofthe desired compound (43.8%, colorless solid), m.p.169.0-170.0° C.

Elemental Analysis for C₁₃ H₁₁ N₄ O₄ SF₃ : Calcd.: C, 41.19; H, 2.95; N,14.89. Found: C, 41.19; H, 2.98; N, 14.63. NMR(200 MHz,CDCl₃ -DMSO-d₆)δ: 2.02(2H,m), 3.34(2H,t,J=6.8 Hz), 4.25(2H,m), 7.85(1H,m),8.15-8.22(2H,m), 8.62(1H,s).

ii) Synthesis of 4,5-dihydro-4-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

To a suspension of 186 mg (0.49 mmol) of 4,5-dihydro-4-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8b-triazacenaphthylene-3,5-dionein 10 ml of methanol was added 0.09 ml of conc. HCl. The solvent wasdistilled off. To the residue was added acetone, and the resulting solidwas washed with acetone and dried to give 177 mg of the desired compound(86.8%, colorless solid), m.p.124.0-125.0° C.

Elemental Analysis for C₁₃ H₁₁ N₄ O₄ SF₃ ·HCl: Calcd.: C, 37.83; H,2.93; N, 13.57. Found: C, 37.63; H, 3.00; N, 13.23. NMR(200 MHz,DMSO-d₆)δ: 1.89(2H,m), 3.28(2H,m), 4.06(2H,m), 7.92(1H,dd,J=8.8,7.4 Hz),8.14(1H,dd,J=7.4,1.0 Hz), 8.30(1H,dd,J=8.8,1.0 Hz), 8.69(1H,s),9.46(1H,br).

EXAMPLE 13 4,5-Dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4,5-dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 1.44 g (14.1 mmol) of 1,5-diaminopentane and 3.64 g(28.2 mmol) of N,N-diisopropylethylamine in 50 ml of acetonitrile wasadded 4.73 g (14.1 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo1,2-a!pyridine in 50 ml of acetonitrile. The mixture was heated for 45minutes under reflux. After cooling, the resulting insolubles werefiltered off. To the filtrate was added 6.04 g (16.9 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was stirred for onehour at room temperature. The solvent was distilled off. To the residuewas added chloroform, and the mixture was washed with an aqueoussolution of sodium hydrogencarbonate, dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purified bymeans of a column chromatography (eluent: ethyl acetate), followed bycrystallization from ethyl acetate. The crystalline product wascollected by filtration, washed with ether and dried to give 2.05 g ofthe desired compound (36.0%, colorless solid), m.p.166.0-167.0° C.

Elemental Analysis for C₁₅ H₁₅ N₄ O₄ SF₃ : Calcd.: C, 44.55; H, 3.74; N,13.86. Found: C, 44.37; H, 3.79; N, 13.81. NMR(200 MHz,CDCl₃ -DMSO-d₆)δ: 1.47-1.83(6H,m), 3.20(2H,t,J=6.6 Hz), 4.17(2H,m),7.84(1H,dd,J=8.4,7.6 Hz), 8.18(1H,d,J=7.6 Hz), 8.18(1H,d,J=8.4 Hz),8.61(1H,s), 8.61(1H,br).

ii) Synthesis of 4,5-dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione·hydrochloride

To a suspension of 469 mg (1.16 mmol) of 4,5-dihydro-4-5-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenathylene-3,5-dionein 20 ml of methanol was added 0.19 ml of conc. HCl, then the solventwas distilled off. To the residue was added acetone, and the resultingsolid substance was washed with acetone and ether, which was dried togive 461 mg of the desired compound (90.2%, colorless solid),m.p.165.0-166.0° C.

Elemental Analysis for C₁₅ H₁₅ N₄ O₄ SF₃ ·HCl: Calcd.: C, 40.87; H,3.66; N, 12.71. Found: C, 40.67; H, 3.69; N, 12.61. NMR(200 MHz,DMSO-d₆)δ: 1.26-1.74(6H,m), 3.14(2H,m), 4.01(2H,m), 7.92(1H,dd,J=8.8,7.2 Hz),8.14(1H,d,J=7.2 Hz), 8.31(1H,d,J=8.8 Hz), 8.69(1H,s), 9.35(1H,br).

EXAMPLE 14 4,5-Dihydro-4-2,2-dimethyl-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4,5-dihydro-4-2,2-dimethyl-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 0.51 g (5.0 mmol) of 1,3-diamino-2,2-dimethylpropaneand 1.29 g (10.0 mmol) of N,N-diisopropylethylamine in 30 ml ofacetonitrile was added a solution of 1.74 g (5.0 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine in 15 ml ofacetonitrile. The mixture was stirred for two hours. To the reactionmixture was added 2.68 g (7.50 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was stirred for onehour at room temperature. The solvent was distilled off. To the residuewas added chloroform, which was washed with an aqueous solution ofsodium hydrogencarbonate, dried over anhydrous magnesium sulfate. Thesolvent was distilled off. The residue was purified by a columnchromatography (eluent: ethyl acetate) to give 1.70 g of the desiredcompound (84.5%, pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.10(6H,s), 2.94(2H,d,J=6.0 Hz), 4.10(2H,s),6.97(1H,br), 7.85(1H,dd,J=8.6,7.6 Hz), 8.22(1H,d,J=7.6 Hz),8.23(1H,d,J=8.6 Hz), 8.69(1H,s).

ii) Synthesis of 4,5-dihydro-4-2,2-dimethyl-3-(trifluoromethanesulfonamido)propan-1-yl!-3H,1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

To a suspension of 1.465 g (3.62 mmol) of 4,5-dihydro-4-2,2-dimethyl-3-(trifluoromethanesulfonamido)propan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dionein 25 ml of methanol was added 0.67 ml of conc. HCl, then the solventwas distilled off. To the residue was added acetone, and the resultingsolid was washed with acetone and ether, dried to give 1.315 g of thedesired compound (82.3%, colorless solid), m.p.196.0-198.0° C.

Elemental Analysis for C₁₅ H₁₅ N₄ O₄ SF₃ ·HCl: Calcd.: C, 40.87; H,3.66; N, 12.71. Found: C, 40.92; H, 3.73; N, 12.87. NMR(200 MHz,DMSO-d₆)δ: 0.95(6H,s), 3.12(2H,d,J=5.6 Hz), 4.01(2H,s), 7.92(1H,dd,J=8.8,7.4Hz), 8.14(1H,dd,J=7.4,1.0 Hz), 8.30(1H,dd,J=8.8,1.0 Hz), 8.70(1H,s),9.26(1H,br).

EXAMPLE 15 4,5-Dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4,5-dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 529 mg (6.00 mmol) of 1,4-diaminobutane and 1.55 g(12.0 mmol) of diisopropylethylamine in 20 ml of acetonitrile was addeda solution of 2.10 g (60.0 mmol) of5-ethoxycarbonyl-2-methyl-trichloroacetylimidazo 1,2-a!pyridine in 10 mlof acetonitrile. The mixture was heated for one hour under reflux. Aftercooling, to which was added 2.58 g (7.22 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was then stirred fortwo hours at room temperature. Insolubles were filtered off, and thefiltrate was concentrated. To the concentrate was added chloroform, andthe mixture was washed with an aqueous solution of sodiumhydrogencarbonate, followed by drying over anhydrous magnesium sulfate.The solvent was distilled off, and the residue was purified by columnchromatography (eluent: ethyl acetate), treated with ether to give 1.04g of the desired compound (42.8%, colorless solid), m.p.183.0-184.0° C.

Elemental Analysis for C₁₅ H₁₅ N₄ O₄ SF₃ : Calcd.: C, 44.55; H, 3.74; N,13.86. Found : C, 44.45; H, 3.79; N, 13.86. NMR(200 MHz,CDCl₃ -DMSO-d₆)δ: 1.60-1.90(4H,m), 2.88(3H,s), 3.26(2H,m), 4.18(2H,t,J=7.0),7.77(1H,dd,J=9.0, 7.4 Hz), 8.03(1H,dd,J=9.0, 1.0 Hz), 8.09(1H,J=7.4, 1.0Hz), 8.56(1H,br).

ii) Synthesis of 4,5-dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

To a suspension of 816 mg (2.02 mmol) of 4,5-dihydro-2-methyl-4-4-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 10 ml ofmethanol was added 0.34 ml of conc. HCl, and the solvent was distilledoff. To the residue was added acetone, and the resulting solid waswashed with acetone, dried to give 790 mg of the desired compound(88.8%, colorless solid), m.p.181.0-182.0° C.

Elemental Analysis for C₁₅ H₁₅ N₄ O₄ SF₃ HCl: Calcd.: C, 40.87; H, 3.66;N, 12.71. Found: C, 40.93; H, 3.66; N, 12.88. NMR(200 MHz,DMSO-d₆) δ:1.46-1.80(4H,m), 2.76(3H,s), 3.19(2H,m), 4.03(2H,t,J=7.0 Hz),7.90(1H,dd,J=8.8,7.4 Hz), 8.08(1H,dd,J=7.4,1.0 Hz), 8.18(1H,dd,J=8.8,1.0Hz), 9.36(1H,br).

EXAMPLE 16 4,5-Dihydro-4-4-(tert-butoxycarbonylamino)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 4.07 g (54.9 mmol) of 1,3-diaminopropane and 5.32 g(41.2 mmol) of N,N-diisopropylethylamine in 70 ml of acetonitrile wasadded a solution of 9.21 g (27.4 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine in 70 ml ofacetonitrile. The mixture was heated for 0.5 hour under reflux. Aftercooling, to which was added 23.96 g (110 mmol) of di-tert-butyldicarbonate, stirred for one hour at room temperature. The solvent wasdistilled off. To the residue was added chloroform. The mixture waswashed with water, then dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified by a columnchromatography (eluent: ethyl acetate), treated with ethyl acetate andn-hexane to give 7.66 g of the desired compound (81.1%, pale yellowsolid), m.p.150.0-151.0° C.

Elemental Analysis for C₁₇ H₂₀ N₄ O₄ : Calcd.: C, 59.29; H, 5.85; N,16.27. Found: C, 59.20; H, 5.97; N, 16.32. NMR(200 OMHz,CDCl₃) δ:1.44(9H,s), 1.93(2H,m), 3.17(2H,m), 4.26(2H,t,J=6.6 Hz), 5.14(1H,br),7.80(1H,dd,J=8.0,6.8 Hz), 8.17(1H,d,J=8.0 Hz), 8.17(1H,d,J=6.8 Hz),8.65(1H,s).

EXAMPLE 17 4,5-Dihydro-4-4-(tert-butoxycarbonylamino)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 13.56 g (153.8 mmol) of 1,4-diaminobutane and 15.00 g(116.1 mmol) of N,N-diisopropylethylamine was added a solution of 25.96g (76.9 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo1,2-a!pyridine in 150 ml of acetonitrile. The mixture was heated for 0.5hour under reflux. After cooling, the resulting insolubles were filteredoff. To the filtrate was added 67.54 g (309.5 mmol) of di-tert-butyldicarbonate. The mixture was stirred for 0.5 hour at room temperature.The solvent was distilled off. To the residue was added chloroform, andthe mixture was washed with water, dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purified bycolumn chromatography (eluent: ethyl acetate), followed bycrystallization from ethyl acetate and n-hexane. The crystalline productwas collected by filtration, washed with n-hexane and dried to give21.72 g of the object product (78.3%, colorless solid), m.p.118.0-119.0°C.

Elemental Analysis for C₁₈ H₂₂ N₄ I₄ : Calcd.: C, 60.32; H, 6.19; N,15.63. Found: C, 60.50; H, 6.16; N, 15.68. NMR(200 MHz,CDCl₃) δ:1.43(9H,s), 1.50-1.85(4H,m), 3.19(2H,m), 4.20(2H,t,J=7.2 Hz),4.63(1H,br), 7.80(1H,dd,J=8.0,6.8 Hz), 8.17(1H,d,J=6.8 Hz),8.17(1H,d,J=8.0 Hz), 8.65(1H,s).

EXAMPLE 18 4,5-Dihydro-4-5-(tert-butoxycarbonylamino)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 5.11 g (50.0 mmol) of 1,5-diaminopentane and 4.85 g(37.5 mmol) of N,N-diisopropylethylamine in 70 ml of acetonitrile wasadded a solution of 8.39 g (25.0 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine in 70 ml ofacetonitrile. The mixture was heated for 0.5 hour under reflux. Aftercooling, the insolubles were filtered off. To the filtrate was added21.83 g (100 mmol) of di-tert-butyl dicarbonate, and the mixture wasstirred for one hour at room temperature. The solvent was distilled off.To the residue was added chloroform. The mixture was washed with waterand dried over anhydrous magnesium sulfate. The solvent was distilledoff, and the residue was purified by column chromatography to give 7.06g of the desired compound (75.8%, pale brown solid), m.p.82.0-83.0° C.

Elemental Analysis for C₁₉ H₂₄ N₄ O₄ : Calcd.: C, 61.28; H, 6.50; N,15.04. Found: C, 60.96; H, 6.41; N, 15.06. NMR(200 MHz,CDCl₃) δ:1.43(9H,s), 1.32-1.65(4H,m), 1.75(2H,m), 3.13(2H,m), 4.18(2H,m),4.60(1H,br), 7.79(1H,dd,J=8.8,7.2 Hz), 8.16(1H,d,J=8.8 Hz),8.16(1H,d,J=7.2 Hz), 8.64(1H,s).

EXAMPLE 19 4,5-Dihydro-4- 4- (2,2,2-trifluoro)ethanesulfonamido!butane-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4,5-dihydro-4-4-(amino)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione·dihydrochloride

To a solution of 3.58 g (10.0 mmol) of 4,5-dihydro-4-4-(tert-butoxycarbonylamino)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dionein 30 ml of methanol was added 15 ml of conc. HCl. The mixture wasstirred for one hour at room temperature. The solvent was distilled off.To the residue were added ethanol and ether. The resulting precipitatewas collected by filtration and dried to give 3.28 g of the desiredcompound (99.1%, white solid), m.p.250.0-252.0° C.

Elemental Analysis for C₁₃ H₁₄ N₄ O₂ ·2HCl·0.3H₂ O Calcd.: C, 46.39; H,4.97; N, 16.64. Found: C, 46.37; H, 5.02; N, 16.51. NMR(200 MHz,D₂ O) δ:1.75(4H,m), 3.04(2H,m), 4.15(2H,m), 8.22(1H,dd,J=9.0,7.4 Hz),8.36(1H,d,J=9.0 Hz), 8.41(1H,d,J=7.4Hz), 8.85(1H,s).

ii) Synthesis of 4,5-dihydro-4- 4-(2,2,2-trifluoro!-ethanesulfonamido!butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a suspension of 994 mg (3.0 mmol) of 4,5-dihydro-4-4-(amino)butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-dihydrochloridein 50 ml of methylene chloride was added, while stirring underice-cooling, 1.47 ml (10.5 mmol) of triethylamine. The mixture wasstirred for 5 minutes, to which was added dropwise 0.66 g (3.6 mmol) of2,2,2-trifluoroethanesulfonyl chloride. The reaction mixture was cooledwith ice for one hour, which was stirred for 19 hours at roomtemperature. The reaction mixture was washed with an aqueous solution ofsodium hydrogencarbonate, which was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purified bycolumn chromatography (eluent: ethyl acetate), followed by washing withether and dried to give 470 mg of the desired compound (38.7%, colorlesssolid), m.p.154.0-155.0° C. NMR(200 MHz,CDCl₃ -DMSO-d₆) δ:1.58-1.90(4H,m), 3.17(2H,m), 3.84(2H,q,J=9.2 Hz), 4.19(2H,t,J=7.0 Hz),7.45(1H,br), 7.83(1H,dd,J=8.6,7.6 Hz), 8.17(1H,d,J=7.6 Hz),8.18(1H,d,J=8.6 Hz), 8.61(1H,s).

iii) Synthesis of 4,5-dihydro-4- 4-(2,2,2-trifluoro)-ethanesulfonamido!butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dionehydrochloride

To a suspension of 440 mg (1.09 mmol) of 4,5-dihydro-4- 4-(2,2,2-trifluoro)ethanesulfonamido!butan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dionein 20 ml of methanol was added 0.15 ml of conc. HCl, and the solvent wasdistilled off. To the residue was added acetone, and the resulting solidproduct was collected by filtration, followed by washing with acetoneand drying to give 435 mg of the desired compound (90.6%, colorlesssolid), m.p.154.0-155.0° C.

Elemental Analysis for C₁₅ H₁₅ N₄ O₄ SF₃ ·HCl·0.5H₂ O Calcd.: C, 40.05;H, 3.81; N, 12.45. Found: C, 40.17; H, 3.62; N, 12.47. NMR(200MHz,DMSO-d₆) ≢: 1.43-1.78(4H,m), 3.03(2H,m), 4.03(2H,m), 4.35(2H,q,J=9.8Hz), 7.74(1H,br), 7.96(1H,dd,J=8.8,7.4 Hz), 8.15(1H,d,J=7.4 Hz),8.31(1H,d,J=8.8 Hz), 8.71(1H,s).

EXAMPLE 20 4- 4-2-(trifluoromethanesulfonamido)ethan-1-yl!phenyl!-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4- 4-2-(trifluoromethanesulfonamido)-ethan-1-yl!phenyl!-4,5-dihydro-3H-1,4,8b-triazaace-naphthylene-3,5-dione

To a solution of 1.18 g (4.4 mmol) of 4-2-(trifluoromethanesulfonamido)ethan-1-yl!aniline and 0.68 g (5.3 mmol)of N,N-diisopropylethylamine in 20 ml of acetonitrile was added asolution of 1.53 g (4.4 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine. The mixturewas heated for 38 hours under reflux. After cooling, and the solvent wasdistilled off. To the residue was added chloroform. The mixture waswashed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled off. The residue was purified by columnchromatography (eluent: ethyl acetate) to give 130 mg of the desiredcompound (6.8%, brown solid).

NMR(200 MHz,CDCl₃) δ: 2.98(2H,t,J=6.6 Hz), 3.62(2H,t,J=6.6 Hz),6.15(1H,br), 7.25(2H,m), 7.42(2H,m), 7.83(1H,dd,J=8.8,7.6 Hz),8.20(1H,dd,J=7.6,1.0 Hz), 8.21(1H,dd,J=8.8,1.0 Hz), 8.58(lH,s).

ii) Synthesis of 4- 4-2-(trifluoromethanesulfonamido)ethan-1-yl!phenyl-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

To a suspension of 130 mg (0.30 mmol) of 4- 4-2-(trifluoromethanesulfonamido)ethan-1-yl!phenyl!-4,5-dihydro-3H-1,4,8b-triazacenaphthylene-3,5-dionein 10 ml of methanol was added 0.1 ml of conc. HCl. The solvent was thendistilled off. To the residue was added acetone. The resulting solidmatter was collected by filtration, washed with acetone and dried togive 82 mg of the desired compound (58.2%, pale brown solid).

NMR(200 MHz,DMSO-d₆) δ: 2.93(2H,t,J=7.2 Hz), 3.48(2H,m), 7.29(2H,d,J=8.4Hz), 7.42(2H,d,J=8.4 Hz), 7.95(1H,dd,J=8.8,7.4 Hz), 8.14(1H,d,J=7.4 Hz),8.34(1H,d,J=8.8 Hz), 8.73(1H,s), 9.63(1H,br).

EXAMPLE 21 4,5-Dihydro-45-(tert-butoxycarbonylamino)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-5-one

A solution of 7.78 g (20 mmol) of 3-(trimethylammonio)methyl!-5-ethoxycarbonylimidazo 1,2-a!pyridine iodide,6.07 g (30 mmol) of 5-tert-butoxycarbonylamino-1-pentylamine and 5.58 ml(40 mmol) of triethylamine was heated for 64 hours under reflux. Thesolvent was distilled off. To the residue was added methylene chloride,washed with water, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified by columnchromatography (eluent: ethyl acetate/ethanol=10:1) to afford 3.93 g ofthe desired compound (54.9%, a pale yellow solid).

NMR(200 MHz,CDCl₃)δ: 1.42(9H,s), 1.27-1.85(6H,m), 3.13(2H,m),3.61(2H,t,J=7.2 Hz), 4.64(1H,br), 5.11(2H,s), 7.21(1H,dd,J=9.0, 7.0 Hz),7.43(1H,s), 7.53(1H,dd,J=7.0, 1.0 Hz), 7.61(1H,dd,J=9.0, 7.0 Hz).

EXAMPLE 22 4,5-Dihydro-45-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-5-one

i) Synthesis of 4,5-dihydro-45-(amino)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-5-one-dihydrochloride

To a solution of 2.24 g (6.25 mmol) of 4,5-dihydro-45-(tert-butoxycarbonylamino)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-5-onein 20 ml of ethanol was added 20 ml of conc. HCl. The mixture wasstirred for 1.5 hour at room temperature. The solvent was distilled offto leave 2.05 g of the desired compound (quant. a pale brown solid).This product was used in the subsequent reaction without furtherpurification. NMR(200 MHz,D₂ O)δ: 1.28-1.90(6H,m), 2.94(2H,t,J=7.2 Hz),3.60(2H,t,J=7.2 Hz), 5.16(2H,s), 7.75(1H,s), 7.82-7.95(3H,m).

ii) 4,5-Dihydro-45-(trifluoromethanesulfonamido)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-5-one

To a suspension of 2.05 g (6.19 mmol) of 4,5-dihydro-45-(amino)pentan-1-yl!-3H-1,4,8b-triazaacenaphthylen-5-one-dihydrochlorideand 4.31 ml (30.9 mmol) of triethylamine in 10 ml of methylenechloride-N,N-dimethylformamide was added 4.42 g (12.4 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was stirred for 4 hourat room temperature. The reaction mixture was washed with water, anddried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was purified by column chromatography (eluent: ethylacetate/ethanol=10:1), followed by recrystallization from ethyl acetateto afford 964 mg of the desired compound (39.9%, a pale yellowcrystals).

NMR(200 MHz,DMSO-D₆): 1.38(2H,m), 1.45-1.75(4H,m), 3.15(2H,t,J=6.8 Hz),3.51(2H,t,J=6.8 Hz), 5.13(2H,s), 7.26(1H,dd,J=9.0, 7.0 Hz),7.39(1H,dd,J=7.0, 1.0 Hz), 7.47(1H,s), 7.66(1H,dd,J=9.0, 1.0 Hz),9.33(1H,br).

EXAMPLE 23 4,5-Dihydro-44-(trifluoromethanesulfonamido)butan-1-yl!-3H-1,4,8b-triazaacenaphthylen-5-one

A solution of 778 mg (2.0 mmol) of 5-ethoxycarbonylimidazo1,2-a!pyridin-8-ylmethyl trimethylammonium iodide, 616 mg (2.4 mmol) of4-trifluoromethanesulfonamido-1-butylamine and 1.12 ml (8.0 mmol) oftriethylamine in 40 ml of acetonitrile was heated for 14 hours underreflux. The solvent was distilled off. To the residue was addedchloroform, and washed with water. The aqueous layer was furtherextracted with chloroform. The chloroform layers were combined, anddried over anhydrous magnesium sulfate. The solvent was distilled off.The residue was crystallized from chloroform. The crystalline productwas collected by filtration, washed with chloroform and dried to afford141 mg (18.8%, colorless crystals) of the desired compound.

Elemental Analysis Calcd for C₁₄ H₁₅ N₄ O₃ SF₃ : Calcd.: C, 44.68; H,4.02; N, 14.89 Found: C, 44.93; H, 3.89; N, 15.13. NMR(200 MHz,CDCl₃-DMSO-d₆)δ: 1.58-1.90(4H,m), 3.27(2H,m), 3.64(2H,m), 5.15(2H,s),7.22(1H,dd,J=9.0, 7.0 Hz), 7.46(1H,s), 7.51(1H,dd,J=7.0, 1.0 Hz),7.62(1H,dd,J=9.0, 1.0 Hz).

EXAMPLE 24 1,2-Dihydro-3-methyl-1- 3-(trifluoromethanesulfonamido)propan-1-yl!-1,4,7b-triazacyclopento cd!inden-2-one·hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-3-(trifluoromethanesulfonamido)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 1.16 g (5.04 mmol) of 1- 3-(amino)propan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopento cd!inden-2-oneand 1.05 ml (7.53 mmol) of triethylamine in 60 ml of methylene chloridewas added, while stirring under ice-cooling, 1.71 g (6.06 mmol) oftrifluoromethane sulfonic acid anhydride. The mixture was stirred for 30minutes at the same temperature. The reaction mixture was washed with anaqueous solution of sodium hydrogencarbonate, dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified by means of a column chromatography (eluent: ethyl acetate) togive 1.15 g of the desired compound (63.0%, pale brown solid),m.p.168.0-169° C.

NMR(200 MHz,CDCl₃) δ: 2.08(2H,m), 2.85(3H,s), 3.33(2H,m), 4.26(2H,m),6.88(1H,d,J=7.4 Hz), 6.97(1H,br), 7.58(1H,d,J=8.6 Hz),7.78(1H,dd,J=8.6,7.4 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1-3-(trifluoromethanesulfonamido)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a suspension of 866 mg (2.39 mmol) of 1,2-dihydro-3-methyl-1-3-(trifluoromethanesulfonamido)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 20 ml of methanol was added 0.24 ml of conc. HCl. Thesolvent was then distilled off. To the residue were added ethanol,acetone and ether. The resulting solid was washed with ether and, thendried to give 844 mg of the desired compound (88.6%, pale yellow solid),m.p.145.0-146° C.

Elemental Analysis for C₁₃ H₁₃ N₄ O₃ SF₃ ·HCl: Calcd.: C, 39.15; H,3.54; N, 14.05. Found: C, 39.13; H, 3.47; N, 14.05. NMR(200 MHz,DMSO-d₆)δ: 2.02(2H,m), 2.78(3H,s), 3.30(2H,m), 4.14(2H,t,J=7.0 Hz),7.52(1H,d,J=7.8 Hz), 7.74(1H,d,J=8.6 Hz), 8.12(1H,dd,J=8.6,7.8 Hz),9.55(1H,br).

EXAMPLE 25 1,2-Dihydro-3-methyl-1- 3-(2,2,2-trifluoro)-ethanesulfonamido!propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1- 3-(2,2,2-trifluoro)ethanesulfonamido!propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 0.43 g (1.87 mmol) of 1-3-(amino)propan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 0.39 ml (2.80 mmol) of triethylamine in 30 ml ofmethylene chloride was added, while stirring under ice-cooling, 0.41 g(2.26 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The mixture wasstirred for 30 minutes at the same temperature. The reaction mixture waswashed with an aqueous solution of sodium hydrogencarbonate, which wasthen dried over anhydrous magnesium sulfate. The solvent was distilledoff, and the residue was purified by column chromatography (eluent:ethyl acetate) to give 412 mg of the desired compound (58.6%, whitepowdery).

NMR(200 MHz,CDCl₃) δ: 2.09(2H,m), 2.84(3H,s), 3.25(2H,m),3.85(2H,q,J=9.0 Hz), 4.25(2H,m), 6.28(1H,br t,J=6.0 Hz), 6.88(1H,d,J=7.4Hz), 7.56(1H,d,J=8.6 Hz), 7.77 (1H,dd,J=8.6,7.4 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1- 3-(2,2,2-trifluoro)ethanesulfonamido!propan-1-yl!-1,4,7b-triazacyclopentocd!inden-2-one-hydrochloride

To a solution of 405 mg (1.08 mmol) of 1,2-dihydro-3-methyl-1- 3-(2,2,2-trifluoro)-ethanesulfonamido!propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 10 ml of methanol was added 0.11 ml of conc. HC1, thenthe solvent was distilled off. To the residue were added ethanol,acetone and ether. The resulting solid was washed with ether and driedto give 436 mg of the desired compound (98.2%, white solid),m.p.157.0-158.0° C.

Elemental Analysis for C₁₄ H₁₅ N₄ O₃ SF₃ ·HCl: Calcd.: C, 40.73; H,3.91; N, 13.57. Found: C, 40.85; H, 3.97; N, 13.38. NMR(200 MHz,DMSO-d₆)δ: 1.99(2H,m), 2.79(3H,s), 3.14(2H,m), 4.12(t,J=7.0 Hz),4.41(2H,q,J=10.0 Hz), 7.55(1H,d,J=7.6 Hz), 7.76(1H,d,J=8.6 Hz),7.92(1H,br), 8.15(1H,dd,J=8.6,7.6 Hz).

EXAMPLE 26 1,2-Dihydro-3-methyl-1-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 1.512 g (5.85 mmol) of 1-5-(amino)pentan!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 1.23 ml (8.82 mmol) of triethylamine in 35 ml ofmethylene chloride was added, while stirring at room temperature, 2.51 g(7.03 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture wasstirred for 14 hours at the same temperature. The reaction mixture waswashed with water, dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified by column chromatography(eluent: ethyl acetate) to give 1.236 g of the desired compound (54.1%,pale yellow solid substance).

Elemental Analysis for C₁₅ H₁₇ N₄ O₃ SF₃ : Calcd.: C, 46.15; H, 4.39; N,14.35. Found: C, 46.29; H, 4.38; N, 14.41. NMR(200 MHz,CDCl₃) δ:1.50(2H,m), 1.74(2H,m), 1.90(2H,m), 2.77(3H,s), 3.33(2H,t,J=6.4 Hz),4.10(2H,t,J=6.6 Hz), 6.82(1H,d,J=7.6 Hz), 7.45(1H,d,J=8.6 Hz),7.71(1H,dd,J=8.6,7.6 Hz)

ii) Synthesis of 1,2-dihydro-3-methyl-1-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentocd!inden-2-one-hydrochloride

To a suspension of 1.195 g (3.06 mmol) of 1,2-dihydro-3-methyl-1-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 15 ml of methanol was added 0.31 ml of conc. HCl, thesolvent was distilled off. To the residue was added acetone and ether.And the resulting solid was washed with ether, dried to give 1.190 g ofthe desired compound (91.0%, white solid), m.p.149.0-150.0° C.

Elemental Analysis for C₁₅ H₁₇ N₄ O₃ SF₃ ·HCl: Calcd.: C, 42.21; H,4.25; N, 13.13. Found: C, 42.03; H, 4.14; N, 13.22. NMR(200 MHz,DMSO-d₆)δ: 1.37(2H,m), 1.55(2H,m), 1.78(2H,m), 2.78(3H,s), 3.11(2H,m),4.07(2H,t,J=7.0 Hz), 7.52(1H,d,J=7.8 Hz), 7.74(1H,d,J=8.6 Hz),8.11(1H,dd,J=8.6,7.8 Hz), 9.33(1H,br).

EXAMPLE 27 1,2-Dihydro-3-methyl-1- 5-(2,2,2-trifluoro)-ethanesulfonamido!pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one·hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1- 5-(2,2,2-trifluoro)ethanesulfonamido!pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 1.630 g (6.31 mmol) of 1-5-(amino)pentyl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 1.32 ml (9.47 mmol) of triethylamine in 30 ml ofmethylene chloride was added, while stirring under ice-cooling, 1.38 g(7.56 mmol) of 2,2,2-trifluoroethanesulfonylchloride. The mixture wasstirred for 30 minutes at the same temperature. The reaction mixture waswashed with an aqueous solution of sodium hydrogencarbonate, which wasthen dried over anhydrous magnesium sulfate. The solvent was distilledoff, and the residue was purified by column chromatography (eluent:ethyl acetate) to give 1.669 g of the desired compound (65.4%, palebrown solid substance).

NMR(200 MHz,CDCl₃) δ: 1.49(2H,m), 1.70(3H,s), 1.88(2H,m), 2.80(3H,s),3.19(2H,m), 3.80(2H,q,J=9.0 Hz), 4.07(2H,t,J=6.4 Hz), 5.87(1H,br t,J=6.0 Hz), 6.82(1H,d,J=7.6 Hz), 7.47(1H,d,J=8.6 Hz),7.71(1H,dd,J=8.6,7.6 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1- 5-(2,2,2-trifluoro)ethanesulfonamido!pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a solution of 1.485 g (3.67 mmol) of 1,2-dihydro-3-methyl-1- 5-(2,2,2-trifluoro)ethanesulfonamido!pentan-1-yl!-1,4,7b-triazacyclopentocd!inden-2-one in 30 ml of methanol was added 0.37 ml of conc. HCl, wasthe solvent was distilled off. To the residue was added ethanol, acetoneand ether, and, the resulting crystals were washed with ether, followedby drying to give 1.632 g of the desired compound (quantitative,colorless crystals), m.p.143.0-145.0° C.

Elemental Analysis for C₁₆ H₁₉ N₄ O₃ SF₃ ·HCl·H₂ O: Calcd.: C, 41.88; H,4.83; N, 12.21. Found: C, 41.73; H, 4.79; N, 12.18. NMR(200 MHz,DMSO-d₆)δ: 1.25-1.60(4H,m), 1.77(2H,m), 2.77(3H,s), 2.96(2H,m), 4.07(2H,t,J=6.8Hz), 4.33(2H,q,J=10.0 Hz), 7.49(1H,d,J=7.4 Hz), 7.72(1H,br), 7.73(1H,d),J=8.8 Hz), 8.08(1H,dd,J=8.8, 7.4 Hz).

EXAMPLE 28 1,2-Dihydro-3-methyl-1-6-(trifluoromethanesulfonamido)hexan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-6-(trifluoromethanesulfonamido)hexane-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 770 mg (2.83 mmol) of 1-6-(amino)hexane-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 0.59 ml (4.23 mmol) of triethylamine in 25 ml ofmethylene chloride was added, while stirring at room temperature, 1.21 g(3.39 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture wasstirred for 14 hours at the same temperature. The reaction mixture waswashed with water, dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified by column chromatography(eluent: ethyl acetate) to give 633 mg of the desired compound (55.4%,pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.31-1.73(6H,m), 1.87(2H,m), 2.81(3H,s),3.31(2H,t,J=6.4 Hz), 4.09(2H,t,J=7.2 Hz), 6.82(1H,d,J=7.6 Hz),7.50(1H,d,J=8.6 Hz), 7.73(1H,dd,J=8.6,7.6 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1-6-(trifluoromethanesulfonamido)hexan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a suspension of 623 mg (1.54 mmol) of 1,2-dihydro-3-methyl-1-6-(trifluoromethanesulfonamido) hexan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 10 ml of methanol was added 0.16 ml of conc. HCl and,then, the solvent was distilled off. To the residue were added acetoneand ether. The resulting solid was washed with ether, dried to give 570mg of the desired compound (83.9%, pale yellow solid).

NMR(200 MHz,DMSO-d₆) δ: 1.25-1.56(6H,m), 1.75(2H,m), 2.75(3H,s),3.11(2H,m), 7.46(1H,d,J=7.8 Hz), 7.70(1H,d,J=8.6 Hz),8.05(1H,dd,J=8.6,7.8 Hz), 9.31(1H,br).

EXAMPLE 29 1,2-Dihydro-3-methyl-1- 6-(2,2,2-trifluoro)ethanesulfonamido!hexan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1- 6-(2,2,2-trifluoro)ethanesulfonamido!hexan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 676 mg (2.48 mmol) of 1-6-(amino)hexyl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 0.52 ml (3.73 mmol) of triethylamine in 30 ml ofmethylene chloride was added, while stirring under ice-cooling, 0.55 g(3.01 mmol) of 2,2,2-trifluoroethanesulfonylchloride, and the mixturewas stirred for 30 minutes at the same temperature range. The reactionmixture was washed with an aqueous solution of sodium hydrogencarbonate,dried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was purified by column chromatography (eluent: ethylacetate) to give 802 mg of the desired compound (77.2%, pale brownsolid).

NMR(200 MHz,CDCl₃) δ: 1.30-1.68(6H,m), 1.86(2H,m), 2.82(3H,s),3.18(2H,m), 3.81(2H,q,J=9.0 Hz), 4.07(2H,t,J=6.8 Hz), 5.48(1H,br t,J=6.0Hz), 6.81(1H,d,J=7.4 Hz), 7.50(1H,d,J=8.6 Hz), 7.71(1H,dd,J=8.6,7.6 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1- 6-(2,2,2-trifluoro)ethanesulfonamido!hexan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a solution of 702 mg (1.68 mmol) of 1,2-dihydro- 3-methyl-1- 6-(2,2,2-trifluoro)ethanesulfonamido!hexan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 15 ml of methanol was added 0.17 ml of conc. HCl, thenthe solvent was distilled off. To the residue were added acetone andether. The resulting crystals were washed with ether and dried to give718 mg of the desired compound (94.1%, colorless crystals),m.p.141.0-143.0° C.

Elemental Analysis for C₁₇ H₂₁ N₄ O₃ SF₃ ·HCl: Calcd.: C, 44.89; H,4.87; N, 12.32. Found: C, 44.79; H, 4,83; N, 12.41. NMR(200 MHz,DMSO-d₆)δ: 1.22-1.50(6H,m), 1.76(2H,m), 2.78(3H,s), 2.96(2H,m), 4.07(2H,t,J=7.0Hz), 4.33(2H,q,J=10.0 Hz), 7.53(1H,d,J=7.8 Hz), 7.71(1H,br),7.75(1H,d,J=8.6 Hz), 8.12(1H,dd,J=8.6,7.8 Hz).

EXAMPLE 30 1,2-Dihydro-3-methyl-1-4-(trifluoromethanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one·hydrochloride

To a solution of 7.05 g (28.9 mmol) of 1-4-(amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 8.04 ml (57.7 mmol) of triethylamine in 300 ml ofmethylene chloride was added, while stirring at room temperature, 20.62g (57.7 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture wasstirred for 8 hours at the same temperature. The reaction mixture waswashed with water, dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified by column chromatography(eluent: ethyl acetate) to give a solid, washed with ether to afford6.17 g of the desired compound (56.8%, pale yellow solid substance),m.p.195.0-196.0° C.

Elemental Analysis for C₁₄ H₁₅ N₄ O₃ SF₃ : Calcd.: C, 44.68; H, 4.02; N,14.89. Found: C, 44.68; H, 3.95; N, 15.02. NMR(200 MHz,CDCl₃) δ:1.78(2H,m), 2.02(2H,m), 2.77(3H,s), 3.44(2H,t,J=6.2 Hz), 4.14(2H,t,J=6.6Hz), 6.82(1H,d,J=7.6 Hz), 7.41(1H,d,J=8.8 Hz), 7.70(1H,dd,J=8.8,7.6 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(trifluoromethanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a suspension of 5.00 g (13.3 mmol) of 1,2-dihydro-3-methyl-1-4-(trifluoromethanesulfonamido)-butan-1-yl!-1,4,7b-triazacyclopentocd!inden-2-one in 100 ml of methanol was added 1.33 ml of conc. HCl,then the solvent was distilled off. To the residue were added methanoland ether, and the resulting solid was collected by filtration, washedwith ether and dried to give 5.38 g of the desired compound (98.2%,colorless solid).

NMR(200 MHz,DMSO-d₆) δ: 1.58(2H,m), 1.83(2H,m), 2.80(3H,s), 3.19(2H,m),4.11(2H,t,J=6.8 Hz), 7.57(lH,d,J=7.8 Hz), 7.77(1H,d,J=8.6 Hz),8.16(1H,dd,J=8.6,7.8 Hz), 9.40(1H,br).

EXAMPLE 31 1,2-Dihydro-3-methyl-1-4-(methanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one·hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-4-(methane-sulfonamido)butan-1-yl!-1,4,7b-triazacyclopentocd!-inden-2-one

To a solution of 977 mg (4.0 mmol) of 1- 4-(amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-oneand 607 mg (6.0 mmol) of triethylamine in 40 ml of methylene chloridewas added, while stirring under ice-cooling, 836 mg (4.8 mmol) ofmethanesulfonic acid anhydride. The mixture was stirred for one hour atroom temperature. The reaction mixture was washed with an aqueoussolution of sodium hydrogencarbonate, dried over anhydrous sodiumhydrogencarbonate. The solvent was distilled off, and the residue wasrecrystallized from methylene chloride-ethanol to give 827 mg of thedesired compound (64.2%, colorless crystals), m.p.183.0-184.0° C.

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(methanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a suspension of 500 mg (1.55 mmol) of 1,2-dihydro-3-methyl-1-4-(methanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-onein 20 ml of methanol was added 0.17 ml of conc. HCl. The solvent wasthen distilled off. The residue was washed with ether to give 555 mg ofthe desired compound (99.6%, colorless solid), m.p.166.0-167.0° C.NMR(200 MHz,DMSO-d₆) δ: 1.53(2H,m), 1.82(2H,m), 2.79(3H,s), 2.86(3H,s),2.96(2H,m), 4.09(2H,t,J=6.8 Hz), 7.00(1H,br), 7.56(1H,d,J=7.6 Hz),7.76(1H,d,J=8.6 Hz), 8.15(1H,dd,J=8.6,7.6 Hz).

EXAMPLE 32 1,2-Dihydro-3-methyl-1-4-(benzamido)butan-1-yl!-1,4,7b-triazacyclopentcdjinden-2-one·hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-4-(benzamido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one

To a solution of 2.44 g (10.0 mmol) of 1-4-(amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 2.09 ml (15.0 mmol) of triethylamine in 80 ml ofmethylene chloride was added, while stirring under ice-cooling, 1.39 ml(12.0 mmol) of benzoyl chloride. The mixture was stirred for 0.5 hour atthe same temperature. The reaction mixture was washed with an aqueoussolution of sodium hydrogencarbonate, dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purified bycolumn chromatography (eluent: ethyl acetate/ethanol=10:1).

NMR(200 MHz,CDCl₃) δ: 1.74(2H,m), 1.95(2H,m), 2.80(3H,s), 3.55(2H,m),4.12(2H,t,J=6.8 Hz), 6.75(1H,br), 6.87(1H,d,J=7.4 Hz), 7.33-7.54(4H,m),7.69(1H,dd,J=8.6,7.4 Hz), 7.75-7.85(2H,m).

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(benzamido)butan-1-yl!-1,4,7b-triazacyclopent-cd!inden-2-one·hydrochloride

To a solution of 3.06 g (8.78 mmol) of 1,2-dihydro-3-methyl-1-4-(benzamido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one in 50 mlof methanol was added 0.88 ml of conc. HCl, then the solvent wasdistilled off. The residue was crystallized from methanol-acetone. Thecrystals were collected by filtration and washed with acetone to give2.90 g of the object product (85.8%, colorless solid), m.p.173.0-175.5°C.

Elemental Analysis for C₂₀ H₂₀ N₄ O₂ ·HCl·0.2H₂ O: Calcd.: C, 61.84; H,5.55; N, 14.42. Found: C, 61.82; H, 5.48; N, 14.34. NMR(200 MHz,DMSO-d₆)δ:1.60(2H,m), 1.82(2H,m), 2.77(3H,s), 3.31(2H,m), 4.12(2H,t,J=6.8 Hz),7.37-7.50(3H,m), 7.54(1H,d,J=7.6 Hz), 7.73(1H,d,J=8.8 Hz), 7.81(2H,m),8.10(1H,dd,J=8.8,7.6 Hz), 8.48(1H,br).

EXAMPLE 33 1,2-Dihydro-3-methyl-1-4-(trifluoroacetamido)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-4-(trifluoroacetamido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one

To a solution of 1.71 g (7.0 mmol) of 1- 4-(amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-oneand 1.46 ml (10.5 mmol) of triethylamine in 50 ml of methylene chloridewas added, while stirring under ice-cooling, 1.76 g (8.4 mmol) oftrifluoroacetic acid anhydride. The mixture was stirred for 3 hours atroom temperature. The reaction mixture was washed with an aqueoussolution of sodium hydrogencarbonate, dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was crystallizedfrom chloroform-ethanol-ether. The crystals were collected by filtrationand washed with ether to give 0.986 g of the desired compound (41.4%,pale yellow crystals). NMR(200 MHz,CDCl₃) δ: 1.73(2H,m), 1.93(2H,m),2.82(3H,s), 3.48(2H,m), 4.12(2H,t,J=6.8 Hz), 6.83(1H,d,J=7.4 Hz),6.91(1H,br), 7.50(1H,d,J=8.6 Hz), 7.73(1H,dd,J=8.6,7.4 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(trifluoroacetamido)butan-1-yl!-1,4,7b-triazacyclopento- cd!inden-2-one·hydrochloride

To a solution of 978 mg (2.87 mmol) of 1,2-dihydro-3-methyl-1-4-(trifluoroacetamido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-onein 15 ml of methanol was added 0.29 ml of conc. HCl. The solvent wasthen distilled off to give 1.084 g of the desired compound (100%, paleyellow solid).

NMR(200 MHz,DMSO-d₆) δ: 1.56(2H,m), 1.77(2H,m), 2.78(3H,s), 3.22(2H,m),4.10(2H,t,J=6.8 Hz), 7.54(1H,d,J=7.8 Hz), 7.75(1H,d,J=8.6 Hz),8.13(1H,dd,J=8.6,7.8 Hz), 9.44(1H,br).

EXAMPLE 34 1,2-Dihydro-3-methyl-1-4-(benzenesulfonamido)butan-1-yl!-1,4,7b-triazacyclopentocd!inden-2-one·hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-4-(benzenesulfonamido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one

To a solution of 1.22 g (5.0 mmol) of 1- 4-(amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopento cd!inden-2-oneand 0.77 ml (6.0 mmol) of triethylamine in 40 ml of methylene chloridewas added, while stirring under ice-cooling, 1.07 g (6.0 mmol) ofbenzenesulfonyl chloride. The mixture was stirred for 0.5 hour at roomtemperature. The reaction mixture was washed with an aqueous solution ofsodium hydrogencarbonate, dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was crystallized frommethylene chloride-ether. The crystals were collected by filtration,which was washed with ether to give 1.09 g (56.8%, grayish white solid)of the desired compound.

NMR(200 MHz,CDCl₃) δ: 1.60(2H,m), 1.92(2H,m), 2.81(3H,s), 3.05(2H,m),4.07(2H,t,J=7.0 Hz), 4.94(1H,br), 6.82(1H,d,J=7.4 Hz), 7.39-7.69(4H,m),7.71(1H,dd,J=8.8,7.4 Hz), 7.80-7.90(2H,m).

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(benzene-sulfonamido)butan-1-yl!-1,4,7b-triazacyclopento-cd!inden-2-one-hydrochloride

To a suspension of 961 mg (2.50 mmol) of 1,2-dihydro-3-methyl-1-4-(benzenesulfonamido)butan-1-yl)-1,4,7b-triazacyclopent cd!inden-2-onein 30 ml of methanol was added 0.42 ml of conc. HCl, and the solvent wasdistilled off. The residue was washed with acetone to give 1.013 g ofthe desired compound (96.3%, colorless solid), m.p.163.0-164.0° C.

Elemental Analysis for C₁₉ H₂₀ N₄ O₃ S·HCl: Calcd.: C, 54.22; H, 5.03;N, 13.31. Found: C, 53.86; H, 5.04; N, 13.15. NMR(200 MHz,DMSO-d₆) δ:1.43(2H,m), 1.75(2H,m), 2.77(2H,m), 2.79(3H,s), 4.03(2H,t,J=6.8 Hz),7.46-7.60(4H,m), 7.64(1H,br), 7.70-7.81(3H,m), 8.13(1H,dd,J=8.6,7.6 Hz).

EXAMPLE 35 1,2-Dihydro-3-methyl-1-4-(ethanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-4-(ethanesulfonamido)butan-1-yl)-1,4,7b-triazacyclopento cd!inden-2-one

To a solution of 1.22 g (5.0 mmol) of 1- 4-(amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopento cd!inden-2-oneand 1.1 ml (7.9 mmol) 5 of triethylamine in 40 ml of methylene chloridewas added, while stirring under ice-cooling, 0.62 ml (6.5 mmol) ofethanesulfonyl chloride. The mixture was stirred for 0.5 hour at roomtemperature. The reaction mixture was washed with an aqueous solution ofsodium hydrogencarbonate, dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was recrystallized frommethylene chloride-ether to give 1.32 g of the desired compound (78.6%,pale brown crystals).

NMR(200 MHz,CDCl₃) δ: 1.36(3H,t,J=7.4 Hz), 1.69(2H,m), 1.97(2H,m),2.82(3H,s), 3.03(2H,q,J=7.4 Hz), 3.22(2H,m), 4.12(2H,t,J=7.0 Hz),4.57(1H,br), 6.86(1H,d,J=7.6 Hz), 7.50(1H,d,J=8.8 Hz),7.72(1H,dd,J=8.8,7.6 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(ethanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopentocd!inden-2-one-hydrochloride

To a suspension of 1.166 g (3.47 mmol) of 1,2-dihydro-3-methyl-1-4-(ethanesulfonamido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-onein 20 ml of methanol was added 0.4 ml of conc. HCl. The solvent was thendistilled off. and the residue was washed with ether to give 1.275 g ofthe desired compound (98.7%, pale brown solid), m.p.144.0-145.0° C.

Elemental Analysis for C₁₅ H₂₀ N₄ O₃ S·HCl: Calcd.: C, 48.32; H, 5.68;N, 15.03. Found: C, 47.94; H, 5.62; N, 14.84. NMR(200 MHz,DMSO-d₆) δ:1.17(3H,t,J=7.2 Hz), 1.52(2H,m,), 1.82(2H,m), 2.80(3H,s),2.96(2H,q,J=7.2 Hz), 4.09(2H,t,J=6.8 Hz), 7.04(1H,br), 7.57(1H,d,J=7.8Hz), 7.77(1H,d,J=8.8 Hz), 8.16(1H,dd,J=8.8,7.8 Hz).

EXAMPLE 36 1,2-Dihydro-3-methyl-1-4-(propan-1-ylsulfonamido)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-4-(propan-1-ylsulfonamido)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 1.22 g (5.0 mmol) of 1- 4-(amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-oneand 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloridewas added, while stirring under ice-cooling, 0.73 ml (6.5 mmol) ofpropan-1-ylsulfonyl chloride. The mixture was stirred for 0.5 hour atroom temperature. The reaction mixture was washed with an aqueoussolution of sodium hydrogencarbonate, which was then dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was recrystallized from methylene chloride-methanol-ether togive 1.313 g of the desired compound (75.0%, pale brown crystals),m.p.150.0-151.0° C.

NMR(200 MHz,CDCl₃) δ: 1.06(3H,t,J=7.4 Hz), 1.60-2.05(6H,m), 2.82(3H,s),2.98(2H,m), 3.22(2H,m), 4.12(2H,t,J=7.0 Hz), 4.48(1H,br),6.86(1H,d,J=7.4 Hz), 7.50(1H,d,J=8.6 Hz), 7.73(1H,dd,J=8.6,7.4 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(propan-1-ylsulfonamido)butan-1-yl!-1,4,7b-triazacyclopento-cd!inden-2-one-hydrochloride

To a suspension of 1.16 g (3.31 mmol) of 1,2-dihydro-3-methyl-1-4-(propan-1-ylsulfonamido)-1-yl!-1,4,7b-triazacyclopent cd!inden-2-onein 30 ml of methanol was added 0.4 ml of conc. HCl. The solvent wasdistilled off to give 1.28 g of the desired compound (100%, pale brownsolid).

NMR(200 MHz,DMSO-d₆) δ: 0.95(3H,t,J=7.4 Hz), 1.43-1.90(6H,m),2.79(3H,s), 2.93(2H,m), 4.09(2H,t,J=6.8 Hz), 7.02(1H,br),7.56(1H,d,J=7.8 Hz), 7.76(1H,d,J=8.6 Hz), 8.15(1H,dd,J=8.6,7.8Hz).

EXAMPLE 37 1,2-Dihydro-3-methyl-1-4-(methoxycarbonylamino)butan-1-yl!-1,4,7b-triazacyclopentocd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-4-(methoxycarbonylamino)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 1.22 g (5.0 mmol) of 1- 4-(amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-oneand 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloridewas added, while stirring under ice-cooling, 0.50 ml (6.5 mmol) ofmethyl chlorocarbonate. The mixture was stirred for 0.5 hour at roomtemperature. The reaction mixture was washed with an aqueous solution ofsodium hydrogencarbonate, which was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue wasrecrystallized from methylene chloride-methanol-ether to give 1.192 g ofthe desired compound (78.9%, colorless crystals), m.p.175-176° C.

NMR(200 MHz,CDCl₃) δ: 1.62(2H,m), 1.90(2H,m), 2.83(3H,s), 3.26(2H,m),3.66(3H,s), 4.10(2H,t,J=7.0 Hz), 4.85(1H,br), 6.84(1H,d,J=7.4 Hz),7.50(1H,d,J=8.6 Hz), 7.22(1H,dd,J=8.6,7.4 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(methoxy-carbonylamino)butan-1-yl!-1,4,7b-triazacyclopento-cd!inden-2-one-hydrochloride

To a suspension of 1.069 g (3.54 mmol) of 1,2-dihydro-3-methyl-1-4-(methoxycarbonylamino)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 30 ml of methanol was added 0.4 ml of conc. HCl. Thesolvent was distilled off to give 1.19 g of the desired compound (99.4%,colorless crystals), m.p.160.0-163.0° C.

EXAMPLE 38 1,2-Dihydro-3-methyl-1- 4-(2,2,2-trifluoro)ethanesulfonamido!butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1- 4-(2,2,2-trifluoro)ethanesulfonamido!butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 5.58 g (22.8 mmol) of 1-4-(amino)propan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 4.78 ml (34.3 mmol) of triethylamine in 200 ml ofmethylene chloride was added, while stirring under ice-cooling, 5.0 g(27.4 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The mixture wasstirred for one hour at the same temperature. The reaction mixture waswashed with an aqueous solution of sodium hydrogencarbonate, dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by means of a column chromatography (eluent: ethylacetate/ethanol=10:1), followed by crystallization from ethylacetate-n-hexane. The crystals were collected by filtration, washed withn-hexane to give 3.89 g of the desired compound (43.6%, colorlesscrystals), m.p.165.0-166.0° C.

Elemental Analysis for C₁₅ H₁₇ N₄ O₃ SF₃ : Calcd.: C, 46.15; H, 4.39; N,14.35. Found: C, 46.15; H, 4.39; N, 14.52.

ii) Synthesis of 1,2-dihydro-3-methyl-1- 3-(2,2,2-trifluoro)ethanesulfonamido!butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a solution of 840 mg (2.15 mmol) of 1,2-dihydro-3-methyl-1- 3-(2,2,2-trifluoro)-ethanesulfonamido!butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 10 ml of methanol was added 0.22 ml of conc. HCl. Thesolvent was distilled off, and the residue was washed with acetone-etherto give 915 mg of the desired compound (99.7%, colorless solid),m.p.116.0-118° C.

EXAMPLE 39 1,2-Dihydro-3-methyl-1-3-(methanesulfonamido)propan-1-yl)-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-3-(methanesulfonamido)propan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one

To a solution of 800 mg (3.47 mmol) of 1-3-(amino)propan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 0.73 ml (5.24 mmol) of triethylamine in 20 ml ofmethylene chloride was added, while stirring under ice-cooling, 726 mg(4.17 mmol) of methanesulfonic acid anhydride. The mixture was stirredfor 0.5 hour at room temperature. The reaction mixture was washed withan aqueous solution of sodium hydrogencarbonate, dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue wasrecrystallized from methylene chloride-ethanol-ether to give 634 mg ofthe desired compound (59.2%, pale yellow crystals).

ii) Synthesis of 1,2-dihydro-3-methyl-3-(methanesulfonamido)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a suspension of 500 mg (1.62 mmol) of 1,2-dihydro-3-methyl-1-3-(methanesulfonamido)propan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-onein 30 ml of methanol was added 0.18 ml of conc. HCl. The solvent wasdistilled off to give 557 mg of the desired compound (99.6%, pale yellowcrystals), m.p.184.0-185.0° C.

Elemental Analysis for C₁₃ H₁₆ N₄ O₃ S·HCl: Calcd.: C, 45.28; H, 4.97;N, 16.25. Found: C, 44.99; H, 4.95; N, 16.16. NMR(200 MHz,DMSO-d₆) δ:1.98(2H,m), 2.78(3H,s), 2.89(3H,s), 3.06(2H,m), 4.13(2H,t,J=7.0 Hz),7.12(1H,br), 7.54(1H,d,J=7.8 Hz), 7.75(1H,d,J=8.6 Hz),8.14(1H,dd,J=8.6,7.8 Hz).

EXAMPLE 40 1,2-Dihydro-3-methyl-1-3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 3,3-dimethyl-1,5-pentanediol

To a solution of 13.38 g (83.5 mmol) of 3,3-dimethylglutaric acid and 90ml (60 mmol) of methanol in 200 ml of 1,2-dichloroethane was added 4.18ml of conc. sulfuric acid at room temperature. The mixture was heatedfor 16 hours under reflux. The reaction mixture was cooled, to which wasadded water. The organic layer was separated, washed with an aqueoussolution of sodium hydrogencarbonate and dried. The solvent wasdistilled off, and the residue was purified by column chromatography(eluent: n-hexane/ethyl acetate=2:1) to give ethyl 3,3-dimethylglutarate. This product was added, at room temperature, to a suspensionof 3.80 g (100 mmol) of lithium aluminum hydride in 250 ml oftetrahydrofuran. The mixture was stirred for 16 hours. Water was addedto this mixture until excess amount of lithium aluminum hydride wasdecomposed. The organic layer was dried, and the resulting precipitatewas filtered off. The solvent was then distilled off to give 10.62 g ofthe desired compound (96.2%, white crystals).

NMR(200 MHz,CDCl₃) δ: 0.95(6H,s), 1.58(4H,t, J=7.0 Hz), 3.74(4H,t,J=7.0Hz).

ii) Synthesis of 1-benzyloxymethoxy-3,3-dimethyl-5-pentanol

To a solution of 7.93 g (60 mmol) of 3,3-dimethyl-1,5-pentandiol and10.45 ml of diisopropylethylamine in 120 ml of dichloromethane wasadded, at room temperature, 8.35 ml (60 mmol) ofbenzylchloromethylether. The mixture was stirred for 3 hours, to whichwas added a saturated aqueous solution of sodium hydrogencarbonate. Themixture was extracted with dichloromethane. The extract was dried, andthen the solvent was distilled off. The residue was purified by columnchromatography (eluent: n-hexane/ethyl acetate=2:1) to give 5.50 g ofthe desired compound (36.3%, colorless oil).

NMR(200 MHz,CDCl₃) δ: 0.95(6H,s), 1.53-1.63(4H,m), 3.61-3.76(4H,m),4.61(2H,s), 4.75(2H,s), 7.35-7.37(5H,m). IR(neat): 3425, 2933, 1454,1380, 1110, 1043, 787, 698 cm⁻¹.

iii) Synthesis of 1-(3,3-dimethyl-5-benzyloxymethoxy-pentyl)phthalimide

To a solution of 5.50 g (21.8 mmol) of3,3-dimethyl-5-benzyloxymethoxy-1-pentanol and 3.14 ml (22.5 mmol) oftriethylamine in 100 ml of dichloromethane was added, at 0C, 1.74 ml(22.5 mmol) of methanesulfonyl chloride. The mixture was stirred for 30minutes at room temperature, to which was added a saturated aqueoussolution of sodium hydrogencarbonate. The mixture was extracted withdichloromethane. The extract was dried, followed by distilling off thesolvent to give 3,3-dimethyl-5-benzyloxymethoxy-1-methanesulfonyl-oxypentane.

NMR(200 MHz,CDCl₃) δ: 0.97(6H,s), 1.61-1.78(4H,m), 2.98(3H,s),3.58-3.66(2H,m), 4.29(2H,t,J=8.0 Hz), 4.59(2H,s), 4.74(2H,s),7.32-7.42(5H,m). IR(neat): 2933, 1479, 1356, 1174, 951, 737, 699 cm⁻¹.

To a solution of the above-mentioned product in 80 ml ofN,N-dimethylformamide was added, at room temperature, 3.70 g (20 mmol)of phthalimide potassium salt. The mixture was stirred for 4 hours at80° C. The reaction mixture was cooled and, then, the solvent wasdistilled off. The residue was dissolved in a mixture of dichloromethaneand a saturated aqueous solution of sodium hydrogencarbonate. Theorganic layer was separated, washed with water and dried, followed bydistilling off the solvent. The residue was purified by columnchromatography (eluent: n-hexane/ethyl acetate=5:1→2:1) to give 5.85 gof the desired compound (70.3%, colorless oily).

NMR(200 MHz,CDCl₃) δ: 1.02(6H,s), 1.58-1.68(4H,m), 3.64-3.75(4H,m),4.61(2H,s), 4.76(2H,s), 7.30-7.37(5H,m), 7.68-7.72(2H,m),7.81-7.85(2H,m). IR(neat): 2954, 1770, 1714, 1400, 1369, 1045, 719, 698cm⁻¹.

iv) Synthesis of 1-(3,3-dimethyl-5-hydroxypentyl)-phthalimide

To a solution of 5.70 g (14.9 mmol) of1-(3,3-dimethyl-5-benzyloxymethoxypentyl)phthalimide in 70 ml ofmethanol was added 3.75 ml (45 mmol) of conc. HCl. The mixture wasstirred for 3 hours at 60° C. The reaction mixture was cooled, and thesolvent was distilled off. The residue was dissolved in 100 ml of water,to which was added 30 ml of 1N aqueous solution of sodium hydroxide. Themixture was extracted with dichloromethane. The extract solution wasdried, and the solvent was distilled off. The residue was purified bycolumn chromatography (eluent: n-hexane/ethyl acetate=2:1→1:2) to give3.63 g of the desired compound (93.2%, white solid).

NMR(200 MHz,CDCl₃) δ: 1.02(6H,s), 1.56-1.67(4H,m), 3.67-3.78(4H,m),7.69-7.73(2H,m), 7.82-7.86(2H,m). IR(KBr): 2954, 1772, 1713, 1400, 1365,719 cm⁻¹.

v) Synthesis of 1,2-dihydro-3-methyl-1-3,3-dimethyl-5-(phthalimido)pentan-1-yl!-1,4,7b-triazacyclopento-cd!inden-2-one

To a solution of 1.57 g (6.0 mmol) of1-(3,3-dimethyl-5-hydroxypentyl)phthalimide and 0.92 ml (6.6 mmol) oftriethylamine in 30 ml of dichloromethane was added, at 0C, 0.51 ml (6.6mmol) of methanesulfonyl chloride. The mixture was stirred for 30minutes at room temperature, to which was added a saturated aqueoussolution of sodium hydrogencarbonate. The mixture was extracted withdichloromethane. The extract was dried, followed by distilling off thesolvent to give 1-(3,3-dimethyl-5-methanesulfonyloxypentyl)phthalimide.

NMR(200 MHz,CDCl₃) δ: 1.05(6H,s), 1.56-1.65(2H,m), 1.81(2H,t,J=7.8 Hz),3.70(3H,s), 3.65-3.74(2H,m), 4.36(2H,t,J=7.8 Hz), 7.69-7.73(2H,m),7.82-7.86(2H,m). IR(neat): 2962, 1770, 1714, 1344, 1171, 947, 716, 527cm⁻¹.

To a suspension of 0.24 g (6.0 mmol) of sodium hydride (60% despersionin oil) in 30 ml of N,N-dimethylformamide was added, at roomtemperature, 1.04 g (6.0 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopento cd!indene. The mixture wasstirred for 10 minutes. To this mixture was added the above-mentionedproduct. The mixture was stirred for 2 hours at 100° C. The reactionmixture was cooled, which was then poured into water, extracted withethyl acetate. The organic layer was washed with water, dried, distilledoff the solvent. The residue was purified by column chromatography(eluent: ethyl acetate→ethyl acetate/ethanol=9:1) to give 1.32 g of thedesired compound (52.8%, pale yellow oil).

NMR(200 MHz,CDCl₃) δ: 1.41(6H,s), 1.67-1.89(4H,m), 2.82(3H,s),3.73-3.82(2H,m), 4.11-4.20(2H,m), 7.02(1H,d,J=7.4 Hz), 7.49(1H,d,J=8.8Hz), 7.70-7.78(3H,m), 7.84-7.88(2H,m). IR(KBr): 2966, 1709, 1626, 1406,1371, 775, 752, 717 cm⁻¹.

vi) Synthesis of 1,2-dihydro-3-methyl-1-3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 1.25 g (3.0 mmol) of 1,2-dihydro-3-methyl-3,3-dimethyl-5-(phthalimido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 30 ml of ethanol was added, at room temperature, 0.44ml (9.0 mmol) of hydrazinemonohydrate. The mixture was heated underreflux. The reaction mixture was cooled, and the resulting precipitateswere filtered off. The solvent was distilled off. The residue wasdissolved in chloroform. The solution was washed with a saturatedaqueous solution of sodium hydrogencarbonate, dried, distilled off thesolvent to give 1,2-dihydro-3-methyl-1-3,3-dimethyl-5-(amino)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one.

NMR(200 MHz,CDCl₃) δ: 1.05(6H,s), 1.49-1.58(2H,m), 1.69-1.78(2H,m),2.75-2.83(4H,m), 4.02-4.11(2H,m), 6.78(1H,d,J=7.4 Hz), 7.48(1H,d,J=8.6Hz), 7.04(1H,d,J=7.4,8.8 Hz).

To a solution of the above-mentioned product and 0.56 ml (4.0 mmol) oftriethylamine in 25 ml of acetonitrile was added, at 0° C., 1.43 g (4.0mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirredfor 12 hours at room temperature. To the reaction mixture was addedwater, to extracted with chloroform. The extract solution was dried, thesolvent was distilled off. The residue was purified by columnchromatography to give 1.03 g of the desired compound (82.1%, paleyellow foam).

NMR(200 MHz,CDCl₃) δ: 1.07(6H,s), 1.72-1.81(4H,m), 2.81(3H,s),3.36-3.44(2H,m), 4.01-4.11(2H,m), 6.83(1H,d,J=7.8 Hz), 7.34-7.38(1H,m),7.51(1H,d,J=9.2 Hz), 7.73(1H,dd,J=7.6,8.8 Hz),;

vii) Synthesis of 1,2-dihydro-3-methyl-1-3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

To a solution of 1.03 g (2.46 mmol) of 1,2-dihydro-3-methyl-1-3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 30 ml of methanol was added 0.29 ml (3.5 mmol) ofconc. HCl. The solvent was distilled off, and the residue wasrecrystallized (solvent: ethanol/diethylether) to give 0.928 g of thedesired compound (82.9%, pale yellow powdery substance),m.p.162.0-165.0° C.

Elemental Analysis for C₁₇ H₂₁ N₄ O₃ S·HCl: Calcd.: C, 44.89; H, 4.87;N, 12.32. Found: C, 44.86; H, 4.89; N, 12.43. NMR(200 MHz,CD₃ OD) δ:1.10(6H,s), 1.62-1.84(4H,m), 2.92(3H,s), 3.22-3.32(2H,m),4.14-4.22(2H,m), 7.56(1H,d,J=7.8 Hz), 7.80(1H,d,J=8.8 Hz),8.32(1H,t,J=8.0 Hz).

EXAMPLE 41 3-Methyl-2-4-(trifluoromethanesulfonamido)butan-1-ylthio!-1,4,7b-triazacyclopentcd!inden-hydrochloride

i) Synthesis of 3-methyl-2-4-(trifluoromethanesulfonamido)butan-1-ylthio!-1,4,7b-triazacyclopentocd!indene

To a solution of 1.30 g (5.0 mmol) of3-methyl-2-(4-(amino)butan-1-ylthio!-1,4,7b-triazacyclopent cd!indeneand 0.84 ml (6.0 mmol) of triethylamine in 40 ml of methylene chloridewas added, while stirring at room temperature, 1.97 g (5.5 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was stirred for 18hours at the same temperature. The reaction mixture was washed with anaqueous solution of sodium hydrogencarbonate, dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified by column chromatography (eluent: ethyl acetate) to give 883 mg(45.1%, pale brown solid).

NMR(200 MHz,CDCl₃) δ: 1.85(2H,m), 2.19(2H,m), 2.90(3H,s), 3.37(2H,m),3.64(2H,t,J=6.0 Hz), 7.76(1H,d,J=7.8 Hz), 7.89(1H,d,J=7.6 Hz),7.99(1H,dd,J=7.8,7.6 Hz), 9.01(1H,br).

ii) Synthesis of 3-methyl-2-4-(trifluoromethanesulfonamido)butan-1-ylthio!-1,4,7b-triazacyclopentcd!indene-hydrochloride

To a suspension of 873 mg (2.22 mmol) of 3-methyl-2-4-(trifluoromethanesulfonamido)butan-1-ylthio!-1,4,7b-triazacyclopentcd!indene in 10 ml of methanol was added 0.23 ml of conc. HCl. Thesolvent was then distilled off. The residue was recrystallized fromethanol-ether to give 762 mg of the desired compound (79.9%, colorlesscrystals), m.p.129.0-131.0° C.

Elemental Analysis for C₁₄ H₁₅ N₄ O₂ S₂ F₃ ·HCl: Calcd.: C, 39.21; H,3.76; N, 13.06. Found: C, 38.92; H, 3.80; N, 13.33.

EXAMPLE 42 4,5-Dihydro-4- 4-(methanesulfonamido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4,5-dihydro-4-4-methanesulfonamido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a suspension of 877 mg (3.0 mmol) of 4-4-(amino)phenylmethyl!-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dioneand 0.63 ml (4.5 mmol) of triethylamine in methylene chloride (60 ml)was added dropwise 0.30 ml (3.9 mmol) of methanesulfonyl chloride whilestirring at room temperature. The mixture was stirred for 72 hours atroom temperature. The solvent was distilled off. To the residue wasadded chloroform, washed with 1N-HCl, and dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purified bycolumn chromatography (eluent: chloroform/methanol=20:1) to afford 274mg of the desired compound (24.7%, a pale yellow solid).

NMR(200 MHz,CDCl₃ -DMSO-d₆)δ: 2.89(3H,s), 5.30(2H,s) 7.23(2H,m),7.51(2H,m), 7.83(1H,dd,J=9.0, 7.2 Hz), 8.17(1H,d,J=9.0 Hz),8.18(1H,d,J=7.2 Hz), 8.63(1H,s), 9.33(1H,br).

ii) Synthesis of 4,5-dihydro-4- 4-(methanesulfonamido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

To a suspension of 248 mg (0.67 mmol) of 4,5-dihydro-4-4-(methanesulfonamido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dionein 15 ml of methanol was added 0.09 ml of conc. HCl. The solvent wasdistilled off. To the residue was added acetone. The resulting solid waswashed with acetone and dried to afford 273 mg of the desired compound(100%, a colorless solid).

EXAMPLE 43 4,5-Dihydro-4- 4-(trifluoromethanesulfonamido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione·hydrochloride

i) Synthesis of 4,5-dihydro-4- 4-(trifluoromethanesulfonamido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a suspension of 1.46 g (5.0 mmol) of 4-4-(amino)phenylmethyl!-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dioneand 1.05 ml (7.5 mmol) of triethylamine in methylene chloride (100 ml)was added dropwise, while stirring under ice-cooling, 1.01 ml (6.0 mmol)of trifluoromethanesulfonic acid anhydride. The mixture was stirred forone hour at room temperature. The reaction mixture was washed with1N-HCl, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the residue was eluted by column chromatography(eluent:chloroform/ethyl acetate=1:1) to afford 502 mg of 4,5-dihydro-4-4-bis(trifluoromethanesulfonyl)imido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione(18.1%, a pale reddish brown solid).

NMR(200 MHz,CDCl₃)δ: 5.40(2H,s), 7.35(2H,m), 7.74(2H,m),7.81(1H,dd,J=9.0, 7.2 Hz), 8.18(1H,d,J=9.0 Hz), 8.19(1H,d,J=7.2Hz),8.67(1H,s). and was further elution (eluent:chloroform/ethylacetate=1:1) afforded 137 mg of the desired compound (6.5%, a pale brownsolid).

NMR(200 MHz,CDCl₃)δ: 5.35(2H,s), 7.24(2H,m), 7.59(2H,m),7.81(1H,dd,J=9.2, 7.2 Hz), 8.18(1H,d,J=9.2 Hz), 8.19(1H,d,J=7.2 Hz),8.66(1H,s).

ii) Synthesis of 4,5-dihydro-4- 4-(trifluoromethanesulfonamido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

To a suspension of 129 mg (0.30 mmol) of 4,5-dihydro-4-4-(trifluoromethanesulfonamido)phenylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 10 ml ofmethanol was added 0.04 ml of conc. HCl. The solvent was distilled off.To the residue was added acetone. The resulting solid was washed withacetone and dried to afford 141 mg of the desired compound (100%, a palebrown solid).

NMR(200 MHz,DMSO-d₆)δ: 5.21(2H,s), 7.20(2H,d,J=8.4 Hz), 7.45(2H,d,J=8.4Hz), 7.94(1H,dd,J=8.8, 7.2 Hz), 8.17(1H,d,J=7.2 Hz), 8.33(1H,d,J=8.8Hz), 8.73(1H,s), 11.78(1H,br).

EXAMPLE 44 4,5-Dihydro-4-1-(tert-butoxycarbonyl)piperidin-4-ylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a suspension of 10.59 g (30.3 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine and 5.09 g(39.4 mmol) of diisopropylethylamine in 200 ml of acetonitrile was added4.15 g (36.3 mmol) of 4-aminomethylpiperidine. The mixture was stirredfor 20 hours at room temperature. To the reaction mixture was addeddropwise 15.87 g (72.7 mmol) of di-tert-butyl dicarbonate, and themixture was stirred for one hour at room temperature. The solvent wasdistilled off. To the residue was added methylene chloride. The mixturewas washed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified by columnchromatography (eluent: ethyl acetate/ethanol=20:1), and treated withethyl acetate and n-hexane to afford 9.10 g (78.1%, a pale yellow solid)of the desired compound.

NMR(200 MHz,CDCl₃)δ: 1.22-1.48(2H,m), 1.45(9H,s), 1.57-1.73(2H,m),2.05(1H,m), 2.55-2.75(2H,m), 3.98-4.22(2H,m), 4.12(2H,d,J=7.0 Hz),7.81(1H,m), 8.13-8.21(2H,m), 8.65(1H,s).

EXAMPLE 45 4,5-Dihydro-4-1-(trifluoroacetyl)piperidin-4-ylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

i) Synthesis of4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylene-3,5-dione-dihydrochloride

To a suspension of 7.99 g (20.8 mmol) of 4,5-dihydro-4-1-(tert-butoxycarbonyl)piperidin-4-ylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dionein 50 ml of ethanol was added dropwise 25 ml of conc.HCl. The mixturewas stirred for two hours at room temperature. The resulting crystallineprecipitates were collected by filtration, washed with ethanol and thenwith ether to afford 7.07 g (87.4%, a colorless solid substance) of thedesired compound

Elemental Analysis Calcd for C₁₅ H₁₆ N₄ O₄ ·2HCl·2H₂ O: Calcd.: C,47.75; H, 5.88; N; 14.85 Found: C, 47.91; H, 5.49; N, 14.84 NMR(200MHz,D₂ O)δ: 1.47-1.72(2H,m), 1.89-2.06(2H,m), 2.21(1H,m), 2.96(2H,m),3.44(2H,m), 4.12(2H,d,J=7.2 Hz), 8.26(1H,dd,J=9.0, 7.2 Hz),8.40(1H,d,J=9.0 Hz), 8.44(1H,d,J=7.2 Hz), 8.89(1H,s).

ii) Synthesis of 4,5-dihydro-4- 1-(trifluoroacetyl)piperidin-4-ylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a suspension of 1.08 g (2.77 mmol) of4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylene-3,5-dione.dihydrochloridein 100 ml of acetonitrile were added 1.93 ml (13.9 mmol) oftriethylamine, 2.0 g (16.4 mmol) of 4-dimethylaminopyridine and 5.25 g(25.0 mmol) of trifluoroacetic acid anhydride. The mixture was stirredfor one hour at room temperature. The solvent was distilled off. To theresidue was added ethyl acetate--tetrahydrofuran. The mixture was washedwith an aqueous solution of sodium hydrogencarbonate, and dried overanhydrous magnesium sulfate. The solvent was distilled off. The residuewas purified by column chromatography (eluent: ethyl acetate), which wasthen recrystallized from ethyl acetate to afford 862 mg (81.7%, acolorless crystals) of the desired compound.

Elemental Analysis Calcd for C₁₇ H₁₅ N₄ O₃ F₃ : Calcd.: C, 53.69; H,3.98; N; 14.73 Found: C, 53.62; H, 3.96; N, 14.69 NMR(200 MHz,CDCl₃)δ:1.50(2H,m), 1.84(2H,m), 2.24(1H,m), 2.77(1H,m), 3.09(1H,m), 4.03(1H,m),4.15(2H,d,J=7.2 Hz), 4.54(1H,m), 7.82(1H,dd,J=9.0, 7.4 Hz),8.19(1H,d,J=7.4 Hz), 8.20(1H,d,J=9.0 Hz), 8.67(1H,s).

EXAMPLE 46 4,5-Dihydro-4-1-(trifluoromethanesulfonyl)piperidin-4-ylmethyl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a suspension of 1.95 g (5.0 mmol) of4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylene-3,5-dione-dihydrochloridein 50 ml of acetonitrile were added 3.5 ml (25.0 mmol) of triethylamineand 8.93 g (25.0 mmol) of N-phenyltrifluoromethanesulfonimide. Themixture was stirred for 66 hours at room temperature. The solvent wasdistilled off. To the residue was added methylene chloride. The mixturewas washed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified by columnchromatography (eluent: ethyl acetate), which was recrystallized fromethyl acetate--ethanol to afford 1.32 g (63.2%, a colorless crystals) ofdesired compound.

NMR(200 MHz,CDCl₃)δ: 1.56(2H,m), 1.83(2H,m), 2.13(1H,m), 3.01(2H,m),3.97(2H,m). 4.16(2H,d,J=7.2 Hz), 7.82(2H,dd,J=8.8, 7.2=Hz),8.19(1H,d,J=7.2 Hz), 8.20(1H,d,J=8.8 Hz), 8.67(1H,s).

EXAMPLE 47 3-Methyl-1-5-(trifluoroacetamido)pentyl!-1,4,7b-triazacyclopent cd!inden-2-one

To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-5-(amino)pentyl!-1,4,7b-triazacyclopent cd!inden-2-one and 1.81 ml (13.0mmol) of triethylamine in 100 ml of acetonitrile was added, whilestirring under ice-cooling, 1.43 ml (12.0 mmol) of trifluoroacetic acidethyl ester. The mixture was stirred for one hour at the sametemperature. The solvent was distilled off. To the residue was addedethyl acetate--tetrahydrofuran. The mixture was washed with an aqueoussaline solution, and dried over anhydrous magnesium sulfate. The solventwas distilled off. The residue was purified by column chromatography(eluent: ethyl acetate), which was recrystallized from ethylacetate-n-hexane to afford 2.57 g (72.6%, a pale yellow crystals) of thedesired compound.

NMR(200 MHz,CDCl₃)δ: 1.44(2H,m), 1.75(2H,m), 1.92(2H,m), 2.82(3H,s),3.39(2H,m), 4.11(2H,t,J=6.6 Hz), 6.83(1H,d,J=7.4 Hz), 6.92(1H,br),7.51(1H,d,J=8.6 Hz), 7.74(1H,dd,J=8.6, 7.4 Hz).

EXAMPLE 48 3-Methyl-1-4-(pentafluoropropanoylamino)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 2.44 g (10.0 mmol) of 3-methyl-1-4-(amino)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one and 1.81 ml(13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, whilestirring at room temperature, 2.31 g (12.0 mmol) of ethyl ester ofpentafluoropropionic acid. The mixture was stirred for 14 hours at thesame temperature. The solvent was distilled off. To the residue wasadded methylene chloride. The mixture was washed with water, which wasdried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was purified by column chromatography (eluent:ethylacetate), and recrystallized from ethyl acetate--hexane to afford 1.53 g(39.1%, a colorless crystals) of the desired compound.

Elemental Analysis Calcd for C₁₆ H₁₅ N₄ O₂ F₅ : Calcd.: C, 49.25; H,3.87; N; 14.35 Found: C, 49.15; H, 3.91; N, 14.21 NMR(200 MHz,CDCl₃)δ:1.73(2H,m), 1.92(2H,m), 2.82(3H,s), 3.50(2H,m), 4.13(2H,t,J=6.8 Hz),6.84(1H,d,J=7.4 Hz), 7.05(1H,br), 7.50(1H,d,J=8.6 Hz),7.73(1H,dd,J=8.6,7.4 Hz).

EXAMPLE 49 3-Methyl-1-5-(pentafluoropropanoylamino)pentan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-5-(amino)pentan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one and 1.81 ml(13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, whilestirring at room temperature, 2.31 g (12.0 mmol) of pentafluoropropionicacid ethyl ester. The mixture was stirred for 4 hours at the sametemperature. The solvent was distilled off. To the residue was addedmethylene chloride, and the mixture was washed with water, and driedover anhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by column chromatography (eluent: ethyl acetate) toafford 2.04 g of the desired compound (50.4%, a pale yellow solid).

NMR(200 MHz,CDCl₃)δ: 1.43(2H,m), 1.75(2H,m), 1.90(2H,m), 2.82(3H,s),3.41(2H,m), 4.10(2H,t,J=6.6 Hz), 6.83(1H,d,J=7.4 Hz), 7.11(1H,br),7.51(1H,d,J=8.6 Hz), 7.74(1H,dd,J=8.6, 7.4 Hz).

EXAMPLE 50 3-Methyl-2-5-(trifluoromethanesulfonamido)pentan-1-ylthio!-1,4,7b-triazacyclopentcd!indene

To a solution of 500 mg (1.82 mmol) of 3-methyl-2-5-(amino)pentan-1-ylthio!-1,4,7b-triazacyclopent cd!indene in 30 ml ofacetonitrile were added 0.51 ml (3.66 mmol) of triethylamine and 1.302 g(3.66 mmol) of N-phenyltrifluoromethanesulfonamide. The mixture wasstirred for two hours at room temperature. The solvent was distilledoff. To the residue was added methylene chloride, which was washed withwater, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the residue was purified by column chromatography(eluent: ethyl acetate) to afford 608 mg (82.1%, a pale yellow solid) ofthe desired compound.

NMR(200 MHz,CDCl₃)δ: 1.55-1.85(4H,m), 1.97(2H,m), 2.90(3H,s),3.39(2H,m), 3.50(2H,t,J=7.0 Hz), 7.69(1H,d,J=7.8 Hz), 7.73(1H,d,J=8.0Hz), 7.95(1H,dd,J=8.0, 7.8 Hz).

EXAMPLE 51 3-Methyl-2-5-(trifluoroacetamido)pentan-1-ylthio!-1,4,7b-triazacyclopent cd!indene

To a solution of 275 mg (1.00 mmol) of 3-methyl-2-5-(amino)pentan-1-ylthio!-1,4,7b-triazacyclopent cd!indene in 30 ml ofacetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 171 mg(1.20 mmol) of ethyl ester of trifluoroacetic acid. The mixture wasstirred for 15 hours at room temperature. The solvent was distilled off.To the residue was added ethyl acetate, which was washed with water, anddried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was purified by column chromatography (eluent: ethylacetate) to afford 267 mg (72.0%, a pale yellow solid) of the desiredcompound.

NMR(200 MHz,CDCl₃)δ: 1.50-2.10(6H,m), 2.90(3H,s), 3.42(2H,m),3.52(2H,t,J=7.0 Hz), 6.56(1H,br), 7.67(1H,d,J=7.8 Hz), 7.73(1H,d,J=8.0Hz), 7.95(1H,dd,J=8.0, 7.8 Hz).

EXAMPLE 52 3-Methyl-2-5-(pentafluoropropanoylamino)pentan-1-ylthio!-1,4,7b-triazacyclopentcd!indene

To a solution of 275 mg (1.00 mmol) of 3-methyl-2-5-(amino)pentan-1-ylthio!-1,4,7b-triazacyclopent cd!indene in 30 ml ofacetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 231 mg(1.20 mmol) of pentafluoropropionic acid ethyl ester. The mixture wasstirred for 15 hours at room temperature, and the the solvent wasdistilled off. To the residue was added ethyl acetate, washed withwater, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the residue was purified by column chromatography(eluent: ethyl acetate) to afford 245 mg (58.1%, a pale brown solid) ofthe desired compound.

NMR(200 MHz,CDCl₃)δ: 1.50-1.80(4H,m), 1.96(2H,m), 2.90(3H,s),3.44(2H,m), 3.52(2H,t,J=7.0 Hz), 6.68(1H,br), 7.67(1H,d,J=7.8 Hz),7.73(1H,d,J=8.0 Hz), 7.95(1H,dd,J=8.0,7.8 Hz).

EXAMPLE 53 3,4-Dihydro-3-5-(tert-butoxycarbonylamino)pentan-1-yl!-1,3,7b-triazacyclopentcd!inden-4-one

To a suspension of 29 mg (0.077 mmol) of 3,4-dihydro-3-5-(phthalimido)pentan-1-yl!-1,3,7b-triazacyclopent cd!inden-4-one in 5ml of ethanol was added 24 mg (0.048 mmol) of hydrazinemonohydrate. Themixture was stirred for three hours under reflux. After cooling, thesolvent was distilled off. To the residue was added 2 ml of chloroform.To the mixture were added 80 mg (0.37 mmol) of di-tert-butyl dicarbonateand 100 mg (0.99 mmol) of triethylamine, and stirred for 14 hours atroom temperature. The reaction mixture was washed with water, and driedover anhydrous magnesium sulfate. The solvent was distilled off. Theresidue was purified by column chromatography (eluent: ethylacetate/ethanol=10:1) to afford 18 mg (67.4%, a colorless solid) thedesired compound.

NMR(200 MHz,CDCl₃)δ: 1.30-1.82(6H,m), 1.44(9H,s), 2.98(1H,m),3.13(2H,m), 4.46(1H,m), 4.58(1H,br), 6.90(1H,dd,J=7.0, 1.2 Hz),7.15(1H,s), 7.17(1H,dd,J=9.2, 7.0 Hz), 7.40(1H,dd,J=9.2, 1.2 Hz).

EXAMPLE 54 3,4-Dihydro-3-5-(trifluoromethanesulfonamido)pentan-1-yl!-1,3,7b-triazacyclopentcd!inden-4-one

To a solution of 18 mg (0.052 mmol) of 3,4-dihydro-3-5-(tert-butoxycarbonylamino)pentan-1-yl!-1,3,7b-triazacyclopentcd!inden-4-one in 1 ml of methanol was added 1 ml of conc.HCl, and themixture was stirred for 15 minutes at room temperature. The solvent wasdistilled off. To the residue was added toluene. The solvent was furtherdistilled off. To the residue were added 3 ml of acetonitrile, 0.2 ml(1.43 mmol) of triethylamine and 100 mg (0.28 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was stirred for 14hours at room temperature. The solvent was distilled off. To the residuewas added chloroform, washed with water, and dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified by column chromatography (eluent: ethyl acetate/ethanol=10:1)to afford 13 mg (66.0%, a colorless solid) of the desired compound.

NMR(200 MHz,CDCl₃)δ: 1.35-1.85(6H,m), 3.05(1H,m), 3.33(2H,m),4.43(1H,m), 6.53(1H,br), 6.97(1H,dd,J=7.0, 1.0 Hz), 7.16(1H,s),7.23(1H,dd,J=9.0, 7.0 Hz), 7.43(1H,dd,J=9.0, 1.0 Hz).

EXAMPLE 554,5-Dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

i) Synthesis of 5- N-(4-trifluoroacetamidobutan-1-yl)aminomethyl)imidazo 1,2-a!pyridine

A suspension of 38.94 g (179.36 mmol) of 5-chloromethylimidazo1,2-a!pyridine-hydrochloride and 31.62 g (358.73 mmol) of1,4-diaminobutane in 500 ml of acetonitrile was heated for one hourunder reflux with stirring. The reaction mixture was cooled to roomtemperature, and 1,4-diaminobutane-dihydrochloride formed as precipitatewas filtered off. To the filtrate were added 21.34 ml (179.36 mmol) oftrifluoroacetic acid ethyl ester and 30 ml (215.23 mmol) oftriethylamine. The mixture was stirred for one hour at room temperature.The solvent was then distilled off under reduced pressure. The residuewas extracted with 500 ml of dichloromethane. The organic layer waswashed with 350 ml of a saturated aqueous saline solution, dried overmagnesium sulfate, and distilled off the solvent under reduced pressure.The residue was purified by silica gel column chromatography(eluent;dichloromethane:methanol=20:1) to afford 29.38 g (52.1%, a paleyellow liquid) of the disired compound.

NMR(200 MHz,CDCl₃)δ: 1.65(4H,m), 2.73(2H,t,J=6.2 Hz), 3.37(2H,m),4.04(2H,s), 6.78(1H,d,J=7.0 Hz), 7.18(1H,dd,J=9.2Hz,7.0 Hz),7.57(1H,d,J=9.2 Hz), 7.67(1H,s), 7.69(1H,s), 7.88(1H,brs,NH). IR(Neat):1714, 1558, 1207, 1153 cm⁻¹

ii) Synthesis of 4,5-dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene

To a solution of 3860 mg (12.28 mmol) of 5-N-(4-trifluoroacetamidobutan-1-yl)aminomethyl!imidazo 1,2-a! pyridine in15 ml of acetic acid was added 13.8 ml (184.21 mmol) of a 37% aqueoussolution of formalin. The mixture was heated for 30 minutes at 100° C.The solvent was distilled off under reduced pressure, and the residuewas dissolved in 100 ml of purified water. To this solution was added 2Nsodium hydroxide to adjust the pH to 8, and extracted with 150 ml ofdichloromethane. The organic layer was washed with 200 ml of a saturatedaqueous saline solution, and dried over magnesium sulfate. The solventwas then distilled off under reduced pressure. The residue was purifiedby silica gel column chromatography (eluent;dichloromethane:methanol=20:1) to afford 2890 mg of the desired compound(72.0%, a white solid).

NMR(200 MHz,CDCl₃)δ: 1.69(4H,m), 2.53(2H,m), 3.40(2H,m), 3.99(2H,s),4.14(2H,s), 6.55(1H,d,J=6.8 Hz), 7.12(1H,dd,J=9.2 Hz, 6.8 Hz),7.39(1H,s), 7.45(1H,d,J=9.2 Hz), 8.14(1H,brs,NH). IR(KBr): 1707, 1562,1260, 1140 cm⁻¹.

iii) Synthesis of 4,5-dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

To a solution of 1100 mg (3.37 mmol) of4,5-dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H,1,4,8b-triazaacenaphthylenein 20 ml of ethanol was added 0.70 ml (8.43 mmol) of 12N hydrochloricacid. The mixture was stirred for one hour at room temperature. Theresulting precipitates were collected by filtration, washed with a smallvolume of ethanol and ether, and dried to afford 1160 mg of the desiredcompound (86.2%, a white crystals).

NMR(200 MHz,DMSO-d₆)δ: 1.50-1.82(4H,m), 3.04(2H,m), 3.23(2H,m),4.64(2H,s), 4.70(2H,s), 7.48(1H,d,J=7.4Hz), 7.95-7.99(2H,m), 8.12(1H,s),9.05(1H,t,J=5.2 Hz). IR(KBr): 1716, 1549, 1224, 1186, 1149 cm⁻¹.

EXAMPLE 564,5-Dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene-3-one-hydrochloride

i) 5- N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-1-yl)aminomethyl!imidazo 1,2-a!pyridine

To a solution of 29.38 g (93.47 mmol) of 5-N-(4-trifluoroacetamidobutan-yl)aminomethyl!imidazo 1,2-a! pyridine in200 ml of ethanol was added 20.40 g (93.47 mmol) of di-tert-butyldicarbonate. The mixture was stirred for one hour at room temperature.The solvent was then distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (eluent;dichloromethane:methanol=20:1) to afford 30.12 g of the desired compound(77.8%, a colorless liquid).

NMR(200 MHz,CDCl₃)δ: 1.35-1.50(13H,m), 3.26(4H,m), 4.71(2H,s),6.69(1H,d,J=6.6 Hz), 7.20(1H,t,J=8.8 Hz), 7.59-7.80(3H,m). IR(Neat):1713, 1686, 1556, 1147 cm⁻¹.

ii) Synthesis of 3-trichloroacetyl-5- N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-1-yl)aminomethyl! imidazo1,2-a!pyridine

To a solution of 7.69 g (18.56 mmol) of 5-N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-1-yl)aminomethyl!imidazo 1,2-a!pyridine and 10.20 g (83.52 mmol) of4-(N,N-dimethylamino)pyridine in 100 ml of THF was added 6.21 ml (55.67mmol) of trichloroacetyl chloride. The reaction mixture was heated for16 hours under reflux. The reaction mixture was poured into ice-water,and extracted with 100 ml of ethyl acetate. The organic layer was washedwith 150 ml of a saturated aqueous saline solution, dried over magnesiumsulfate, and distilled off the solvent under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent;chloroform) to afford 4.98 g of the desired compound (48.0%, a paleyellow amorphous).

NMR(200 MHz,CDCl₃)δ: 1.26(9H,s), 1.68(4H,m), 3.43(4H,m), 4.51(lH,s),4.68(1H,s), 6.95(1H,brs,NH), 7.11(1H,d,J=7.0 Hz), 7.65-7.78(2H,m),8.69(0.5H,s), 8.97(0.5H,s). IR(KBr): 1701, 1514, 1178, 1153 cm⁻¹.

iii) Synthesis of 4,5-dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-one

To a solution of 2.60 g (4.64 mmol) of 3-trichloro acetyl-5-N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-1-yl)aminomethyl!imidazo1,2-a!pyridine in 20 ml of ethanol was added 1.90 ml (23.22 mmol) of 12NHCl. The mixture was stirred for one hour at room temperature. Thesolvent and excess volume of hydrochloric acid were distilled off underreduced pressure. The residue was dissolved in a mixture of 20 ml ofpurified water and 20 ml of ethanol. To this solution was added a 2Naqueous solution of sodium hydroxide to neutralize. This solution wasextracted with 100 ml of dichloromethane. The organic layer was washedwith 100 ml of a saturated aqueous saline solution, dried over magnesiumsulfate, and distilled off the solvent under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent;dichloromethane:methanol=20:1) to afford 1.26 g of the desired compound(75.9%, pale yellow amorphous).

NMR(200 MHz,CDCl₃)δ: 1.74(4H,m), 3.48(2H,m), 3.63(2H,m), 5.03(2H,s),6.77(1H,d,J=7.0 Hz), 7.28(1H,brs,NH), 7.34(1H,dd,J=9.2 Hz, 7.0 Hz),8.15(1H,s). IR(KBr): 1702, 1643, 1207, 1159 cm⁻¹

iv) Synthesis of4,5-dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

To a solution of 1.13 g (3.32 mmol) of4,5-dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-onein 20 ml of ethanol was added 0.42 ml (4.98 mmol) of 12N hydrochloricacid. The mixture was concentrated under reduced pressure. The resultingcrystals was collected by filtration, which was washed with a smallvolume of ethanol and ether to afford 560 mg of the desired compound(44.8%, a white crystals.

NMR(200 MHz,DMSO-d₆)δ: 1.63(4H,m), 3.27(2H,m), 3.53(2H,m), 5.25(2H,s),7.43(1H,d,J=7.4 Hz), 7.85(1H,d,J=8.2 Hz), 8.02(1H,dd,J=8.2,7.4 Hz),8.61(1H,s), 9.06(1H,t,NH,J=5.4 Hz). IR(KBr): 1709, 1653, 1255 cm⁻¹.

EXAMPLE 574,5-Dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

i) Synthesis of 5-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl!imidazo1,2-a!pyridine

A suspension of 15.13 g (69.69 mmol) of 5-chloromethylimidazo1,2-a!pyridine-hydrochloride and 12.29 g (139.38 mmol) of1,4-diaminobutane in 150 ml of acetonitrile was heated for one hourunder reflux while stirring. The reaction mixture was cooled to roomtemperature. The resulting precipitates of1,4-diaminobutane-dihydrochloride were filtered off. To the filtratewere added 20.61 ml (139.38 mmol) of ethyl ester of pentafluoropropionicacid and 19.43 ml (139.38 mmol) of triethylamine. The mixture wasstirred for one hour at room temperature. The solvent was then distilledoff under reduced pressure, and the residue was extracted with 200 ml ofdichloromethane. The organic layer was washed with 150 ml of a saturatedaqueous saline solution, dried over magnesium sulfate, and distilled offthe solvent. The residue was purified by silica gel columnchromatography (eluent; dichloromethane:methanol=20:1) to afford 13.61 gof the desired compound (53.6%, a pale yellow liquid).

NMR(200 MHz,CDCl₃)δ: 1.54-1.75(4H,m), 2.72(2H,t,J=6.6 Hz),3.39(2H,q,J=6.6 Hz), 4.03(2H,s), 6.78(1H,d,J=6.8 Hz), 7.17(1H,dd,J=9.0Hz, 6.8 Hz), 7.54(1H,d,J=9.0 Hz), 7.64(1H,s), 7.69(1H,s),8.32(1H,brs,NH). IR(Neat): 1710, 1550, 1221, 1161 cm⁻¹.

ii) Synthesis of 4,5-dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene

To a solution of 2620 mg (7.19 mmol) of 5-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl!imidazo1,2-a!pyridine in 10 ml of acetic acid was added 8.1 ml (107.88 mmol) ofa 37% aqueous solution of formalin. The mixture was heated for 30minutes at 100° C. The solvent was distilled off under reduced pressure,and the residue was dissolved in 100 ml of purified water. To thissolution was added 2N sodium hydroxide to adjust the pH to 8, andextracted with 100 ml of dichloromethane. The organic layer was washedwith 100 ml of a saturated aqueous saline solution, dried over magnesiumsulfate, and distilled off the solvent under reduced pressure. Theresidue was purified by silica gel column chromatography to afford 2250mg of the desired compound (83.2%, a pale yellow liquid).

NMR(200 MHz,CDCl₃)δ: 1.64-1.74(4H,m), 2.53(2H,m), 3.42(2H,m),3.97(2H,s), 4.10(2H,s), 6.54(1H,d,J=6.8 Hz), 7.11(1H,dd,J=9.2,6.8 Hz),7.34(1H,s), 7.41(1H,d,J=9.2 Hz), 8.63(1H,brs,NH). IR(Neat): 1718, 1545,1221, 1169 cm⁻¹.

iii) Synthesis of 4,5-dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

To a solution of 2230 mg (5.93 mmol) of4,5-dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylenein 35 ml of ethanol was added 1.22 ml (14.31 mmol) of 12N hydrochloricacid. The mixture was stirred for one hour at room temperature. Theresulting precipitates was collected by filtration, washed with a smallvolume of ethanol and ether, and dried to afford 2120 mg of the desiredcompound (76.9%, white crystals).

NMR(200 MHz,CDCl₃)δ: 1.23-1.34(2H,m), 1.36-1.93(2H,m), 3.20-3.30(4H,m),4.85(2H,s), 4.94(2H,s), 7.54(1H,m), 8.00(2H,m), 8.21(1H,s),9.66(1H,t,NH,J=5.4 Hz) IR(Neat): 1712, 1549, 1223, 1167 cm⁻¹.

EXAMPLE 58 Synthesis of4,5-dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

i) Synthesis of 5- N-tert-butoxycarbonyl-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl!imidazo 1,2-a! pyridine

To a solution of 12.41 g (34.06 mmol) of 5-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl!imidazo1,2-a!pyridine in 100 ml of ethanol was added 7.44 g (34.06 mmol) ofdi-tert-butyl dicarbonate. The mixture was stirred for one hour at roomtemperature. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography(eluent;dichloromethane:methanol=20:1) to afford 11.78 g of the desiredcompound (74.5%, a colorless liquid).

NMR(200 MHz,CDCl₃)δ: 1.22-1.72(13H,s), 3.06-3.53(4H,m), 4.71(2H,s),6.70(1H,d,J=6.6 Hz), 7.20(1H,t,J=8.6 Hz), 7.45-7.95(4H,m). IR(Neat):1712, 1687, 1523, 1221, 1165 cm⁻¹.

ii) Synthesis of 3-trichloroacetyl-5- N-tert-butoxycarbonyl-N-(4-pentafluoropropionamidobutan-1-yl)amino methyl!imidazo1,2-a!pyridine

To a solution of 11.78 g (25.36 mmol) of 5-NNtert-butoxycarbonyl-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl!imidazo1,2-a!pyridine and 13.94 g (114.36 mmol) of4-(N,N-dimethylamino)pyridine in 250 ml of chloroform was added 8.50 ml(76.09 mmol) of trichloroacetyl chloride. The mixture was heated for 16hours under reflux. The reaction mixture was poured into ice-water, andextracted with 100 ml of chloroform. The organic layer was washed with200 ml of a saturated aqueous saline solution, dried over magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:chloroform) to afford 6.80 g of the desired compound (44.0%, a paleyellow liquid).

NMR(200 MHz,CDCl₃)δ: 1.00-1.45(9H,s), 1.55-1.80(4H,m), 3.25-3.55(4H,m),4.51(2H,s), 7.10(1H,d,J=7.4 Hz), 7.72(1H,t,J=8.8 Hz), 7.83(1H,d,J=8.6Hz), 8.97(1H,s). IR(Neat): 1724, 1678, 1670, 1219, 1157 cm⁻¹.

iii) Synthesis of 4,5-dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-one

To a solution of 5.00 g (8.2 mmol) of 3-trichloroacetyl-5-(N-tert-butoxycarbonyl-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl!imidazo 1,2-a!pyridine in 100 ml of ethanolwas added 3.4 ml (41.0 mmol) of 12N hydrochloric acid. The mixture wasstirred for one hour at room temperature. The solvent and an excessvolume of hydrochloric acid were distilled off under reduced pressure.The residue was dissolved in a mixture of 50 ml of purified water and 50ml of ethanol. The solution was neutralized with 2N aqueous solution ofsodium hydroxide. This solution was extracted with 150 ml ofdichloromethane. The organic layer was washed with 150 ml of a saturatedaqueous saline solution, dried over magnesium sulfate, and distilled offthe solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent; dichloromethane:methanol=20:1) toafford 2.11 g of the desired compound (66.1%, a pale yellow solid).

NMR(200 MHz,CDCl₃)δ: 1.62-1.85(4H,m), 3.42-3.54(2H,m), 3.55-3.68(2H,m),5.02(2H,s), 6.76(1H,d,J=7.0 Hz), 7.27-7.56(1H,m), 7.52(1H,brs,NH),7.53(1H,d,J=9.2 Hz), 8.15(1H,s). IR(KBr): 1702, 1646, 1543, 1220, 1161cm⁻¹.

iv) Synthesis of 4,5-dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

To a solution of 840 mg (2.15 mmol) of4,5-dihydro-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene-3-onein 15 ml of ethanol was added 0.27 ml (3.23 mmol) of 12N hydrochloricacid. The mixture was concentrated under reduced pressure. The resultingcrystalline precipitates were collected by filtration, and washed with asmall volume of ethanol and ether to afford 662 mg of the desiredcompound (72.1%, white crystals).

NMR(200 MHz,DMSO-d₆)δ: 1.58(4H,m), 3.26(2H,m), 3.55(2H,t,J=6.2 Hz),5.24(2H,s), 7.42(1H,d,J=7.4 Hz), 7.84(1H,d,J=9.2 Hz),7.99(1H,dd,J=7.4,9.2 Hz), 8.63(1H,s), 9.59(1H,t,NH,J=5.4 Hz). IR(KBr):1718, 1636, 1548, 1224, 1163 cm⁻¹.

EXAMPLE 59 Synthesis of1-(1-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl)-3-methyl-2H-1,4,7b-triazacyclopentcd!inden-2-one

i) Synthesis of 1-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethylp-toluenesulfonate

To a solution of 10.18 g (50.58 mmol) of (S)-1-butoxycarbonylprolinoland 8.00 g (101.16 mmol) of pyridine in 100 cc of dichloromethane wasadded 9.64 g (50.58 mmol) of p-toluenesulfonyl chloride. The reactionmixture was stirred for two hours at room temperature, to which wasadded 100 cc of dichloromethane. The mixture was washed with 200 cc ofpurified water, then with 200 cc of a saturated aqueous saline solution.The organic layer was dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent; hexane:ethyl acetate=1:1) to afford15.28 g of the desired compound (85.0%, a colorless liquid).

NMR(200 MHz,CDCl₃)δ: 1.37(9H,s), 1.78-1.93(4H,m), 2.44(3H,s),3.25-3.31(2H,m), 3.89-4.09(3H,m), 7.34(2H,d,J=8.0 Hz), 7.77(2H,d,J=8.0Hz). IR(Neat): 1722, 1666, 1166 cm⁻¹.

ii) Synthesis of1-(1-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl)-3-methyl-2H-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 5.85 g (33.81 mmol) of3-methyl-2H-1,4,7b-triazacyclopent cd!inden-2-one in 100 cc of DMF wasadded, while stirring under ice-cooling, 1.35 g (33.81 mmol) of sodiumhydride (purity 60%) under the atmosphere of argon. The mixture wasstirred for 30 minutes under the atmosphere of argon. To the reactionmixture was added at 0C, under the atmosphere of argon, a solution of14.42 g (40.57 mmol) of1-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl p-toluenesulfonate in10 cc of DMF. The mixture was heated for 3 hours at 100° C. under theatmosphere of argon. The reaction mixture was poured into ice-water, andextracted with 500 cc of ethyl acetate. The organic layer was washedwith water three times, and further with 300 cc of a saturated aqueoussaline solution, dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: ethyl acetate) to afford 7.54 g ofthe desired compound (64.9%, a pale yellow liquid).

NMR(200 MHz,CDCl₃)δ: 1.48(9H,s), 1.89(4H,m), 2.83(3H,s), 4.23(3H,m),7.10(d,J=7.4 Hz) and 6.79(d,J=7.4 Hz) for 1H, 7.49(1H,d,J=8.8 Hz),7.70(1H,dd,J=7.4,8.8 Hz). IR(Neat): 1710, 1679, 1166 cm⁻¹.

EXAMPLE 601,2-Dihydro-3-methyl-1-(1-trifluoromethanesulfonyl-2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of1,2-dihydro-3-methyl-1-(2-(S)-pyrrolidin-2-ylmethyl-1,4,7b-triazacyclopentcd!inden-2-one-dihydrochloride

A solution of 3.42 g (10 mmol) of1-(1-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl)-3-methyl-2H-1,4,7b-triazacyclopentcd!inden-2-one in mixture of 25 cc of ethanol and 2 cc of 1Nhydrochloric acid was stirred for one hour at room temperature. Thesolvent was distilled off under reduced pressure. To the residue wasadded 20 cc of toluene. The solvent was distilled off under reducedpressure. This procedure was repeated twice. The residue was driedsufficiently to afford 4.11 g of a crude product (100%, a while solid).This crude product was used in the subsequent reaction withoutpurification.

NMR(200 MHz,D₂ O)δ: 1.74-2.38(4H,m), 2.83(3H,s), 3.17-3.40(2H,m),4.00(1H,m), 4.49(2H,d,J=6.4 Hz), 7.52(1H,d,J=8.0 Hz), 7.75(1H,d,J=8.8Hz), 8.23(1H,dd,J=8.0 Hz, 8.8 Hz). IR(KBr): 3433, 1720, 1646, 1591 cm⁻¹.

ii) Synthesis of 1,2-dihydro-3-methyl-1-(1-trifluoromethanesulfonyl-2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 786 mg (2.5 mmol) of1,2-dihydro-3-methyl-1-(2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one-dihydrochloride in 15 cc of acetonitrile was added, whilestirring under ice-cooling, 1.4 cc (10.0 mmol) of triethylamine,followed by addition of 5.14 g (6.25 mmol) ofN-phenyltrifluoromethanesulfonimide. The reaction mixture was stirredfor two hours at room temperature. The solvent was distilled off underreduced pressure. The residue was purified by silica gel chromatography(eluent: ethyl acetate) to afford 751 mg of the desired compound (80.2%,a pale yellow liquid).

NMR(200 MHz,CDCl₃)δ: 2.09(1H,m), 2.82(3H,s), 3.59(2H,m), 4.34(3H,m),7.02(1H,d,J=7.6 Hz), 7.53(1H,d,J=8.6 Hz), 7.78(1H,dd,J=7.6, 8.6 Hz).IR(Neat): 1729, 1650, 1385 cm⁻¹.

iii) Synthesis of 1,2-dihydro-3-methyl-1-(1-trifluoromethanesulfonyl-2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

In a solvent consisting of 20 cc of ethanol and 0.1 cc of 12Nhydrochloric acid was dissolved 800 mg (2.14 mmol) of1,2-dihydro-3-methyl-1-(1-trifluoromethanesulfonyl)-2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopentcdjindene. The solvent was distilled off under reduced pressure. Theresidue was dried to afford 880 mg of the desired compound (100%, awhite solid).

NMR(200 MHz,DMSO)δ: 1.98-2.18(5H,m), 2.85(3H,s), 3.50(2H,m), 4.19(2H,m),7.58(1H,d,J=7.6 Hz), 7.81(1H,d,J=8.4 Hz), 8.25(1H,dd,J=7.6,8.4 Hz).IR(KBr): 1733, 1651, 1385 cm⁻¹.

EXAMPLE 61 1,2-Dihydro-3-methyl-1-1-(2,2,2-trifluoroethanesulfonyl)-2-(s)-pyrrolidin-2-ylmethyl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-1-(2,2,2-trifluoroethanesulfonyl)-2-(S)-pyrrolidin-2-ylmethyl!-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 786 mg (2.5 mmol) of1,2-dihydro-3-methyl-1-(2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one-dihydrochloride in 15 cc of dichloromethane was added,while stirring under ice-cooling, 1.4 cc (10.0 mmol) of triethylamine,and added 0.33 cc (3.0 mmol) of 2,2,2-trifluoroethanesulfonyl choride.The reaction mixture was stirred for one hour at room temperature. Thesolvent was then distilled off under reduced pressure. The residue waspurified by silica gel chromatography (eluent: ethyl acetate) to afford651 mg of the desired compound (67.1%, a white solid).

NMR(200 MHz,CDCl₃)δ: 2.00(3H,m), 2.26(1H,m), 3.21-3.58(2H,m),3.86(2H,q,J=9.2 Hz), 4.12-4.34(3H,m), 7.10(1H,d,J=7.6 Hz),7.52(1H,d,J=8.6 Hz), 7.77(1H,dd,J=7.6,8.6 Hz). IR(Neat): 1731, 1651,1358 cm⁻¹.

ii) Synthesis of 1,2-dihydro-3-methyl-1-1-(2,2,2-trifluoroethanesulfonyl)-2-(S)-pyrrolidin-2-ylmethyl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

In a solvent consisting of 20 cc of ethanol and 0.1 cc of 12Nhydrochloric acid was dissolved 626.1 mg (1.61 mmol) of1,2-dihydro-3-methyl-1-1-(2,2,2-trifluoroethanesulfonyl!-2-(S)-pyrrolidin-2-ylmethyl!-1,4,7b-triazacyclopentcd!inden-2-one. The solvent was distilled off under reduced pressure.The residue was dried to afford 685 mg of the desired compound (100%, awhite solid).

NMR(200 MHz,DMSO-d₆)δ: 1.89-2.07(4H,m), 2.85(3H,s), 3.44(2H,m),4.16-4.38(3H,m), 4.48(2H,g,J=10.1 Hz), 7.60(1H,d,J=8.0 Hz),7.81(1H,d,J=8.0 Hz), 8.26(1H,t,J=8.0 Hz). IR(KBr): 1738, 1650, 1589,1358 cm⁻¹.

EXAMPLE 62 4,5-Dihydro-4- 2-4-(trifluoromethanesulfonamido)phenyl!ethan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

i) Synthesis of 4,5-dihydro-4- 2- 4-(trifluoromethanesulfonamide)phenyl!ethan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a suspension of 1.53 g (5.0 mmol) of 4,5-dihydro-4- 2-4-(amino)phenyl!ethan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione and1.05 ml (7.5 mmol) in methylene chloride (150 ml) was added dropwise,while stirring under ice-cooling, 1.21 ml (7.2 mmol) oftrifluoromethanesulfonic acid anhydride. The mixture was stirred for 14hours at room temperature. The reaction mixture was washed with 1N-HCl,which was dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the residue was eluted by column chromatography(eluent: ethyl acetate/methylene chloride=1:1) to afford 245 mg of4,5-dihydro-4- 2- 4-bis(trifluoromethanesulfonyl)imido!phenyl!ethan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione(8.6%, a pale yellow solid).

NMR(200 MHz,CDCl₃)δ: 3.10(2H,m), 4.43(2H,m), 7.34(2H,d,J=8.4 Hz),7.49(2H,d,J=8.4 Hz), 7.80(1H,dd,J=8.8, 7.6 Hz), 8.16(1H,dd,J=7.6, 1.0Hz), 8.18(1H,dd,J=8.8, 1.0 Hz), 8.67(1H,s). IR(KBr): 1710, 1666, 1632,1444, 1340, 1290, 1223, 1163, 1128 cm⁻¹

And further elution (eluent: ethyl acetate/methylene chloride=1:1)afforded 77 mg of the desired compound (3.5%, a pale yellow solid).

NMR(200 MHz,DMSO-d₆)δ: 2.90(2H,m), 4.22(2H,m), 7.20(2H,d,J=8.4 Hz),7.33(2H,d,J=8.4 Hz), 7.91(1H,dd,J=8.8, 7.4 Hz), 8.13(1H,dd,J=7.4, 1.0Hz), 8.31(1H,dd,J=8.8, 1.0 Hz), 8.67(1H,s). IR(KBr): 1707, 1662, 1633,1510, 1371, 1340, 1284, 1209, 1167, 1137 cm⁻¹

ii) Synthesis of 4,5-dihydro-4- 2- 4-(trifluoromethanesulfonamido)phenyl!ethan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride

To a suspension of 59 mg (0.13 mmol) of 4,5-dihydro-4- 2-4-(trifluoromethanesulfonamido)phenyl!ethan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3,5-dionein 5 ml of methanol was added 0.05 ml of conc. hydrochloric acid. Thesolvent was distilled off to afford 64 mg of the desired compound (100%,a pale yellow solid).

NMR(200 MHz,DMSO-d₆)δ: 2.91(2H,m), 4.22(2H,m), 7.21(2H,d,J=8.4 Hz),7.34(2H,d,J=8.4 Hz), 7.93(1H,dd,J=8.8, 7.4 Hz), 8.14(1H,dd,J=7.4, 1.0Hz), 8.32(1H,dd,J=8.8, 1.0 Hz), 8.69(1H,s). IR(KBr): 3099, 1724, 1681,1649, 1348, 1209, 1144 cm⁻¹

EXAMPLE 63 3,4-Dihydro-3-5-(tert-butoxycarbonylamino)penten-1-yl!-2-methyl-1,3,7b-triazacyclopentcd!inden-4-one

To a suspension of 355 mg (0.91 mmol) of 3,4-dihydro-3-5-(phthalimido)pentan-1-yl!-2-methyl-1,3,7b-triazacyclopentcd!inden-4-one in 15 ml of ethanol was added 229 mg (4.57 mmol) ofhydrazinemonohydrate. The mixture was stirred for two hours whileheating under reflux. After cooling the resulting precipitates werefiltered off, and the filtrate was concentrated. To the concentrate wasadded 30 ml of chloroform. To the mixture were added 1.00 g (4.58 mmol)of di-tert-butyl dicarbonate and 0.38 ml (2.73 mmol) of triethylamine.The mixture was stirred for one hour at room temperature. The reactionmixture was washed with water and dried over anhydrous magnesiumsulfate. The solvent was distilled off. The residue was purified bycolumn chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 244mg of the desired compound (74.4%, a pale yellow foam).

NMR(200 MHz,CDCl₃)δ: 1.20-1.80(6H,m), 1.44(9H,s), 2.07(3H,s),3.02(1H,m), 3.10(2H,m), 4.34(1H,m), 4.54(1H,br), 6.98(1H,dd,J=6.8, 1.2Hz), 7.16(1H,dd,J=9.0, 6.8 Hz), 7.32(1H,dd,J=9.0, 1.2 Hz).

EXAMPLE 64 3,4-Dihydro-2-methyl-3- 5-(trifluoromethanesulfonamido)pentan-1-yl!-1,3,7b-triazacyclopent cd!inden-4-one

To a solution of 228 mg (0.64 mmol) of 3,4-dihydro-3-5-(tert-butoxycarbonylamino)pentan-1-yl!-2-methyl-1,3,7b-triazacyclopentcd!inden-4-one in 5 ml of methanol was added 5 ml of conc. hydrochloricacid. The mixture was stirred for 30 minute at room temperature. Thesolvent was distilled off. To the residue was added toluene, and thesolvent was distilled off. To the residue were added 20 ml ofacetonitrile, 0.89 ml (6.39 mmol) of triethylamine and 1.14 g (3.19mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirredfor 20 hours at room temperature. The solvent was distilled off. To theresidue was added chloroform. The mixture was washed with water anddried over magnesium sulfate. The solvent was distilled off. The residuewas purified by column chromatography (eluent: ethylacetate/ethanol=10:1) to afford 13 mg of the desired compound (5.2%, apale yellow solid).

NMR(200 MHz,CDCl₃)δ: 1.20-1.80(6H,m), 2.08(3H,s), 3.02(1H,m),3.18(2H,m), 4.33(1H,m), 7.02(1H,dd,J=6.8, 1.2 Hz), 7.19(1H,dd,J=9.0, 6.8Hz), 7.32(1H,dd,J=9.0, 1.2 Hz), 8.64(1H,br)

EXAMPLE 654,5-Dihydro-4-(3-trifluoromethanesulfonamidopropan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

i) Synthesis of 3-carbomethoxy-5-N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl!imidazo1,2-a!pyridine

To a solution of 581 mg (1.00 mmol) of 3-trichloro acetyl-5-N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl!imidazo1,2-a!pyridine in 5.0 ml of methanol was added 0.46 ml (2.00 mmol) of a25% methanol solution of sodium methylate. The mixture was stirred for10 minutes at room temperature. The reaction mixture was poured intoice-water, which was neutralized with 1N HCl. The mixture was extractedwith 50 ml of chloroform. The organic layer was washed with 50 ml of asaturated aqueous saline solution, and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: chloroform) toafford 462 mg of the desired compound (93.4%, a pale yellow liquid).

NMR(200 MHz,CDCl₃)δ: 1.32(9H,s), 1.83(2H,m), 3.35(2H,brs),3.49(2H,t,J=6.0 Hz), 3.93(3H,s), 4.85(2H,s), 6.84(1H,d,J=7.2 Hz),7.49(1H,t,J=7.2 Hz), 7.70(1H,d,J=8.8 Hz), 8.36(1H,s). IR(Neat): 1699,1680, 1512, 1471, 1419 cm⁻¹

ii) Synthesis of 3-hydroxymethyl-5-N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl!imidazo1,2-a!pyridine

To a solution of 396 mg (0.80 mmol) of 3-carbomethoxy-5-N-tert-butoxycarbonyl-N-(3-trifluoromethane-sulfonamidopropan-1-yl)aminomethyl!imidazo1,2-a!pyridine in a mixture of 5.0 ml of THF and 1.0 ml of methanol wasadded, at room temperature, 87.12 mg (4.00 mmol) of lithium borohydridewith small portions. The mixture was heated for 30 minutes under reflux.The reaction mixture was cooled to room temperature, and poured intoice-water. The mixture was neutralized with 1N HCl, and extracted with50 ml of chloroform. The organic layer was washed with 50 ml of asaturated aqueous saline solution, which was dried over magnesiumsulfate. The solvent was then distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent;chloroform:methanol=20:1) to afford 269 mg of the desired compound (72%,a pale yellow liquid).

NMR(200 MHz,CDCl₃)δ: 1.40(9H,s), 1.83(2H,m), 3.35(2H,t,J=6.4 Hz),3.49(2H,t,J=6.4 Hz), 4.90(2H,s), 5.18(2H,s), 6.59(1H,d,J=7.4 Hz),7.12-7.25(1H,m), 7.42-7.52(2H,m). IR(Neat): 1695, 1497, 1470 cm⁻¹

iii) Synthesis of4,5-dihydro-4-(3-trifluoromethanesulfonamidopropan-1-yl)-3H-1,4,8b-triazaacenaphthylene

To a solution of 233 mg (0.50 mmol) of 3-hydroxymethyl-5-N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl!imidazo1,2-a!pyridine in 5.0 ml of chloroform was added 0.36 ml (2.50 mmol) oftrimethylsilyl iodide. The mixture was stirred for 18 hours at roomtemperature. The reaction mixture was poured into ice-water, which wasneutralized with a saturated aqueous solution of sodiumhydrogencarbonate, and extracted of the desired compound with 50 ml ofchloroform. The organic layer was washed with 50 ml of a saturatedaqueous saline solution and dried over magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (eluent;chloroform:methanol=20:1) to afford 109 mg of the desired compound(62.8%, a pale yellow liquid).

NMR(200 MHz,CDCl₃)δ: 1.82(2H,m), 2.68(2H,m), 3.43(2H,m), 3.91(2H,s),4.01(2H,s), 6.53(1H,d,J=6.8 Hz), 7.10(1H,dd,J=9.2,6.8 Hz), 7.27(1H,s),7.39(1H,d,J=9.2 Hz), 8.27(1H,brs,NH) IR(Neat): 1637, 1552, 1450, 1363cm⁻¹

iv) Synthesis of 4,5-dihydro-4-(3-trifluoromethanesulfonamidopropan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride

To a solution of 248 mg (0.72 mmol) of4,5-dihydro-4-(3-trifluoromethanesulfonamidopropan-1-yl)-3H-1,4,8b-triazaacenaphthylenein 5.0 ml of ethanol was added 0.18 ml (2.16 mmol) of 12N HCl. Themixture was stirred, and concentrated under reduced pressure. resultingprecipitates were washed with a small volume of ethanol and ether toafford 253 mg of the desired compound (84.2%, a white solid).

NMR(200 MHz,DMSO-d₆)δ: 2.02(2H,m), 3.17(4H,m), 4.85(2H,s), 4.93(2H,s),7.54(1H,m), 7.99-8.02(2H,m), 8.19(1H,s), 9.39(1H,t,NH,J=5.6 Hz)IR(Neat): 3430, 1660, 1550, 1441 cm⁻¹

EXAMPLE 66 4,5-Dihydro-4-4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl!-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

i) Synthesis of 5-N-(4-(2-trifluorommethanesulfonamidoethan-yl)phenyl!aminomethyl!imidazo1,2-a!pyridine

A solution of 6.51 g (30.00 mmol) of 5-chloromethylimidazo1,2-a!pyridine, 8.05 g (30.00 mmol) of1-amino-4-(2-trifluoromethanesulfonamidoethan-1-yl)benzene and 8.4 ml(60.00 mmol) of triethylamine was heated for 3 hours under reflux. Thereaction mixture was cooled to room temperature to cause formation oftriethylamine hydrochloride, which was filtered off. The filtrate wasconcentrated under reduced pressure, and the concentrate was extractedwith 150 ml of chloroform. The organic layer was washed with 150 ml of asaturated aqueous saline solution. The organic layer was dried overmagnesium sulfate. The solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (eluent;ethyl acetate:ethanol=20:1) to afford 9.11 g of the desired compound(76.2%, a colorless liquid).

NMR(200 MHz,CDCl₃)δ: 2.37(2H,brs), 3.45(2H,t,J=8.2 Hz), 4.77(2H,brs),6.48(2H,d,J=8.4 Hz), 6.64(2H,d,J=8.4 Hz), 6.85(1H,d,J=6.8 Hz),7.21-7.29(1H,m), 7.74(1H,d,J=7.6 Hz), 7.77(1H,s), 7.89(1H,s). IR(Neat):1628, 1518, 1387 cm⁻¹.

ii) Synthesis of 5- N-tert-butoxycarbonyl-N-4-(2-trifluoromethansulfonamidoethan-1-yl!phenylaminomethyl! imidazo1,2-a!pyridine

To a solution of 2130 mg (5.35 mmol) of 5- N-4-(2-trifluoromethansulfonamidoethan-1-yl)phenyl!aminomethyl!imidazo1,2-a!pyridine in 30 ml of ethanol was added 1167 mg (5.35 mmol) ofdi-tert-butyl dicarbonate. The mixture was stirred for 2 hours at roomtemperature. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent; ethylacetate: ethanol=20:1) to afford 2.0 g of the desired compound (75.0%,colorless amorphous).

NMR(200 MHz,CDCl₃)δ: 1.50(9H,s),2.39(2H,brs), 3.48(2H,t,J=8.0 Hz),4.78(2H,brs), 6.50(1H,brs,NH), 6.75(2H,d,J=8.4 Hz), 6.84(1H,d,J=7.0 Hz),7.15(2H,d,J=8.4 Hz), 7.25-7.29(1H,m), 7.75(1H,d,J=8.4 Hz), 7.77(1H,s),7.92(1H,s). IR(Neat): 1710, 1630, 1522, 1390 cm⁻¹

iii) Synthesis of 3-trichloroacetyl-5- N-tert-butoxy carbonyl-N-4-(2-trifluoromethanesulfonamidoethan-1-yl) phenyl!aminomethyl!imidazo1,2-a!pyridine

To a solution of 2.00 g of 5- N-tert-butoxycarbonyl-N-4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl! aminomethyl!imidazo1,2-a!pyridine and 1.47 g (12.04 mmol) of 4-(N,N-dimethylamino)pyridinein 20 ml of chloroform was added dropwise 1.34 ml (12.04 mmol) oftrichloroacetyl chloride at room temperature. The reaction mixture washeated for 18 hours under reflux. The reaction mixture was poured intoice-water. The mixture was neutralized with a saturated aqueous solutionof sodium hydrogencarbonate, and extracted with 100 ml of chloroform.The organic layer was washed with 100 ml of purified water three timesand further with 100 ml of a saturated aqueous saline solution, anddried over magnesium sulfate. The solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: chloroform) to afford 1415 mg of the desiredcompound (54.8%, a yellow liquid).

NMR(200 MHz,CDCl₃)δ: 1.23(9H,s), 2.38(2H,brs), 3.48(2H,t,J=8.0 Hz),4.58(2H,brs), 6.52(1H,brs,NH), 6.80(2H,d,J=8.4 Hz), 7.24(1H,d,J=7.0 Hz),7.19(2H,d,J=8.4 Hz), 7.76-7.80(1H,m), 7.81(1H,d,J=8.4 Hz), 8.96(1H,s)IR(KBr): 1710, 1690, 1525, 1360 cm⁻¹

iv) Synthesis of 4,5-dihydro-4- 4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl!-3H-1,4,8b-triazaacenaphthylen-3-one

To a solution of 644 mg (1.00 mmol) of 3-trichloroacetyl-5-N-tert-butoxycarbonyl-N-4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl!aminomethyl!imidazo1,2-a! pyridine in 5 ml of chloroform was added dropwise 0.29 ml (2.00mmol) of trimethylsilyl iodide at room temperature. The reaction mixturewas stirred for 30 minutes at room temperature, and poured intoice-water. The mixture was neutralized with a saturated aqueous solutionof sodium hydrogencarbonate. To the mixture was added 50 ml ofchloroform for extraction of the desired compound. The organic layer waswashed with 50 ml of a saturated aqueous saline solution, and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (eluent;chloroform:methanol=20:1) to afford 195.7 mg of the desired compound(46.1%, a pale yellow solid).

NMR(200 MHz,CDCl₃)δ: 2.36(2H,brs), 3.45(2H,t,J=8.0 Hz), 5.08(2H,s),6.51(1H,brs,NH), 6.85(2H,d,J=8.4 Hz), 6.89(2H,d,J=7.0 Hz),7.19(2H,d,J=8.4 Hz), 7.34-7.40(1H,m), 7.75(1H,d,J=8.4 Hz), 8.12(1H,s)IR(KBr): 1708, 1661, 1535, 1430 cm⁻¹

v) Synthesis of 4,5-dihydro-4- 4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl!-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride

To a solution of 85 mg (0.2 mmol) of 4,5-dihydro-4-4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl!-3H-1,4,8b-triazaacenaphthylen-3-onein 5.0 ml of ethanol was added 0.04 ml (0.5 mmol) of 12N HCl. Themixture was stirred at room temperature, and concentrated under reducedpressure. The resulting precipitates were collected by filtration, andwashed with a small volume of ethanol and ether to afford 64 mg of thedesired compound (69.4%, a pale yellow solid).

NMR(200 MHz,DMSO-d₆)δ: 2.22(2H,brs), 3.38(2H,t,J=6.8 Hz), 5.28(2H,s),7.25(2H,d,J=8.4 Hz), 7.49(2H,d,J=7.2 Hz), 7.59(2H,d,J=8.4 Hz),7.94-8.00(1H,m), 8.35(1H,d,J=8.4 Hz), 8.72(1H,s) IR(KBr): 1720, 1665,1443, 1385 cm⁻¹

EXAMPLE 67 1-1-(tert-Butoxycarbonyl)piperidin-4-ylmethyl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 735 mg (4.24 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-one in 15 ml ofDMF was added, while stirring under ice-cooling, 187 mg (4.68 mmol) of60% sodium hydride (dispersion in oil). The mixture was stirred for 20minutes at the same temperature. To the mixture was added a solution of1.18 g (4.24 mmol) of 4-bromomethyl-1-tert-butoxycarbonylpiperidine in 5ml of DMF. The mixture was stirred for one hour at 100° C. Aftercooling, the reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with water and brine, dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by column chromatography (eluent: ethyl acetate) togive 988 mg of the desired compound (62.8%, pale yellow solid).

NMR(200 MHz,CDCl₃)δ: 1.41(2H,m), 1.45(9H,s), 1.71(2H,m), 2.11(1H,m),2.68(2H,m), 2.83(3H,s), 3.95(2H,d,J=7.2 Hz), 4.15(2H,m), 6.79(1H,d,J=7.6Hz), 7.50(1H,d,J=8.6 Hz), 7.72(1H,dd,J=8.6, 7.6 Hz).

EXAMPLE 68 1,2-dihydro-1-1-(trifluoromethanesulfonyl)piperidin-4-ylmethyl!-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one hydrochloride

i) Synthesis of1,2-dihydro-1-(piperidin-4-ylmethyl)-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 3.65 g (9.85 mmol) of 1-1-(tert-butoxycarbonyl)piperidin-4-ylmethyl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one in 30 ml of methanol was added 15 ml of conc. HCl. Themixture was stirred for 1.5 hours at room temperature. The solvent wasdistilled off. To the residue was added chloroform and 2N agueoussolution of sodium hydroxide to make alkaline. The mixture was extractedwith chloroform. The extract was dried over anhydrous magnesium sulfate.The solvent was distilled off to give 2.316 g of the desired compound(86.9%, pale yellow solid). This product was used in the subsequentreaction without further purification.

ii) Synthesis of 1,2-dihydro-1-1-(trifluoromethanesulfonyl)piperidin-4-ylmethyl!-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 1.09 g (4.03 mmol) of1,2-dihydro-1-(piperidin-4-ylmethyl)-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one and 0.84 ml (6.03 mmol) of triethylamine in 30 ml ofmethylene chloride was added 1.73 g (4.84 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was stirred for 14hours at room temperature. The reaction mixture was washed with water,dried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was purified by column chromatography (eluent: ethylacetate) to give 522 mg of the desired compound (32.2%, pale yellowsolid).

NMR(200 MHz,CDCl₃)δ: 1.50(2H,m), 1.87(2H,m), 2.20(1H,m), 2.83(3H,s),3.02(2H,m), 3.99(2H,d,J=7.0 Hz), 4.00(2H,m), 6.77(1H,d,J=7.4 Hz),7.51(1H,d,J=8.6 Hz), 7.73(1H,dd,J=8.6, 7.4 Hz).

iii) Synthesis of 1,2-dihydro-1- 1-(trifluoromethanesulfonyl)piperidin-4-ylmethyl!-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one.multidot.hydrochloride

To a suspension of 494 mg (1.23 mmol) of 1,2-dihydro-1-1-(trifluoromethanesulfonyl)piperidin-4-ylmethyl!-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one in 15 ml of methanol was added 0.13 ml of conc. HCL. Thesolvent was distilled off. The residue was treated with acetone anddiethylether to give 526 mg of the desired compound (97.6%, colorlesssolid). m.p. 150-152° C.

Elemental Analysis for C₁₆ H₁₇ N₄ O₃ SF₃ ·HCl·H₂ O: Calcd.: C, 42,06; H,4.41; N, 12.26 Found: C, 42.07; H, 4.27; N, 12.07 NMR(200 MHz,DMSO-d₆)δ:1.38(2H,m), 1.84(2H,m), 2.16(1H,m), 2.79(3H,s), 3.14(2H,m), 3.84(4H,m),7.57(1H,d,J=7.6 Hz), 7.76(1H,d,J=8.4 Hz), 8.14(1H,dd,J=8.4, 7.6 Hz).

EXAMPLE 69 1-1-(tert-Butoxycarbonyl)piperidin-4-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

The title compound was synthesized in the same manner as example 67.

NMR(200 MHz,CDCl₃)δ: 1.52(9H,s), 2.00(2H,m), 2.17(2H,m), 2.83(3H,s),2.94(2H,m), 4.37(2H,m), 4.72(1H,m), 6.90(1H,d,J=7.8 Hz), 7.50(1H,d,J=8.4Hz), 7.69(1H,dd,J=8.4, 7.8 Hz).

EXAMPLE 70 1- 2-1-(tert-Butoxycarbonyl)piperidin-4-yl!ethan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

The title compound was synthesized in the same manner as example 67.

NMR(200 MHz,CDCl₃)δ: 1.18(2H,m), 1.46(9H,s), 1.50(1H,m),1.70-1.86(4H,m), 2.68(2H,m), 2.83(3H,s), 4.11(4H,m), 6.78(1H,d,J=7.6Hz), 7.50(1H,d,J=8.6 Hz), 7.71(1H,dd,J=8.6, 7.6 Hz).

EXAMPLE 71 1,2-Dihydro-1- 2- 1-(trifluoromethanesulfonyl)piperidin-4-yl!ethan-1-yl!-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

The title compound was synthesized in the same manner as Example 68.m.p. 169-170° C.

Elemental Analysis for C₁₇ H₁₉ N₄ O₃ SF₃ ·HCl: Calcd.: C, 45.09; H,4.45; N, 12.37 Found: C, 44.95; H, 4.42; N, 12.13 NMR(200 MHz,DMSO-d₆)δ:1.23(2H,m), 1.58(1H,m), 1.76(2H,m), 1.91(2H,m), 2.75(3H,s), 3.11(2H,m),4.10(2H,t,J=7.2 Hz), 7.46(1H,d,J=7.6 Hz), 7.70(1H,d,J=8.8 Hz),8.04(1H,dd,J=8.8, 7.6 Hz).

EXAMPLE 72 1,2-Dihydro-3-methyl-1- 4-(N-methyl-N-trifluromethanesulfoneamide)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1,2-dihydro-3-methyl-1-4-(N-methyl-N-trifluoromethanesulfonamide)butan-1-yl!-1,4,7b-triazacyclopentcd!indene-2-one

To a solution of 1.129 g (3.0 mmol) of 1,2-dihydro-3-methyl-1-4-(trifluoromethanesulfonamide)butan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 30 ml of DMF was added, while stirring underice-cooling, 144 mg (3.6 mmol) of 60% sodium hydride (dispersion inoil). The mixture was stirred for 15 minutes at the same temperature. Tothe mixture was added 0.56 ml of methyl iodide. The mixture was stirredfor 14 hours at room temperature. The reaction mixture was poured intowater and extracted with ethyl acetate. The mixture was washed withwater and dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the residue was purified by column chromatography(eluent: ethyl acetate) to give 170 mg of the desired compound (14.5%,pale brown solid).

NMR(200 MHz,CDCl₃)δ: 1.65-2.02(4H,m), 2.83(3H,s), 3.01(3H,d,J=1.2 Hz),3.42(2H,m), 4.13(2H,t,J=6.8 Hz), 6.85(1H,d,J=7.4 Hz), 7.51(1H,d,J=8.6Hz), 7.73(1H,dd,J=8.6, 7.6 Hz).

ii) Synthesis of 1,2-dihydro-3-methyl-1-4-(N-methyl-N-trifluoromethanesulfonamide)butan-1-yl!-1,4,7b-triazacyclopentcd!indene-2-one-hydrochloride

To a solution of 168 mg (0.43 mmol) of 1,2-dihydro-3-methyl-1-4-(N-methyl-N-trifluoromethenesulfonamide)butan-1-yl!-1,4,7b-triazacyclopent cd!indene-2-one in 5 mlof methanol was added 0.05 ml of conc. HCl. The solvent was distilledoff. The residue was washed with acetone to give 163 mg of the desiredcompound (88.6%, yellow solid). m.p. 133-135° C.

Elemental Analysis for C₁₅ H₁₇ N₄ O₃ SF₃ ·HCl: Calcd.: C, 42.21; H,4.25; N, 13.13 Found: C, 42.09; H, 4.26; N, 12.95 NMR(200 MHz,DMSO-d₆)δ:1.58-1.85(4H,m), 2.78(3H,s), 2.99(3H,d,J=1.2 Hz), 3.40(2H,m),4.12(2H,t,J=6.4 Hz), 7.53(1H,d,J=7.6 Hz), 7.74(1H,d,J=8.6 Hz),8.11(1H,dd,J=8.6, 7.6 Hz).

EXAMPLE 73 1-4-(tert-Butoxycarbonylamino)butan-1-yl!-1,2-dihydro-1,4,7b-triazacyclopentcd!inden-2-one

To a solution of 1.67 g (8.87 mmol) of4-tert-butoxycarbonylamino-1-butylamine and 1.53 g (11.8 mmol) ofN,N-diisopropylethylamine in 30 ml of acetonitrile was added 1.762 g(5.91 mmol) of 5-chloro-3-trichloroacetylimidazo 1,2-a!pyridine. Themixture was heated for 17 hours under reflux with stirring. The solventwas distilled off. To the residue was added chloroform. The residue waswashed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified by columnchromatography (eluent: ethyl acetate) to give 453 mg of 5-4-(tert-butoxycarbonylamino)butan-1-ylamino!-3-4-(tert-butoxycarbonylamino)butan-1-ylcarbamoyl!imidazo1,2-a!pyridine(14.8%, pale brown solid) as fration 1,

NMR(200 MHz,CDCl₃)δ: 1.44(18H,s), 1.40-2.00(8H,m), 3.05-3.32(6H,m),3.49(2H,m), 4.83(2H,br), 5.90(1H,d), 6.99(1H,d,J=8.6 Hz), 7.03(1H,br),7.31(1H,dd,J=8.6, 7.8 Hz), 8.06(1H,s), 8.87(1H,br). and to give 583 mgof the disired compound (29.8%, pale brown solid) as fraction 2,

NMR(200 MHz,CDCl₃)δ: 1.43(9H,s), 1.62(2H,m), 1.91(2H,m), 3.22(2H,m),4.12(2H,t,J=7.2 Hz), 4.89(1H,br), 6.96(1H,d,J=7.4 Hz), 7.63(1H,d,J=8.8Hz), 7.77(1H,dd,J=8.8, 7.4 Hz), 8.33(1H,s). and was eluted (eluent:ethyl acetate/ethanol=10:1) to give 508 mg of 5-chloro-3-4-tert-butoxycarbonylamino) butan-1-ylcarbamoyl!imidazo1,2-a!pyridine(23.4%, pale brown solid).

NMR(200 MHz,CDCl₃)δ: 1.43(9H,s), 1.50-1.80(4H,m), 3.19(2H,m),3.52(2H,m), 4.64(1H,br), 6.52(1H,br), 6.98(1H,dd,J=7.2, 1.0 Hz),7.28(1H,dd,J=9.0, 7.2 Hz), 7.63(1H,dd,J=9.0, 1.0 Hz), 7.86(1H,s).

EXAMPLE 74 1,2-Dihydro-1-4-(trifluoromethanesulfonamide)butan-1-yl)-1,4,7b-triazacyclopentcd!inden-2-one-hydrochloride

i) Synthesis of 1-4-(amino)butan-1-yl!-1,2-dihydro-1,4,7b-triazacyclopentcd!inden-2-one-dihydrochloride

To a solution of 548 mg (1.66 mmol) of 1-4-tert-butoxycarbonylamino)butan-1-yl)-1,2-dihydro-1,4,7b-triazacyclopentcd!inden-2-one in 10 ml of methanol was added dropwise 10 ml of conc.HCl. The mixture was stirred for one hour at room temperature. Thesolvent was distilled off. To the residue was added acetone. Theresulting solid was collected by filtration and washed with acetone togive 400 mg of the desired compound (79.5%, grayish white solid).

Elemental Analysis for C₁₂ H₁₄ N₄ O·2HCl: Calcd.: C, 44.87; H, 5.65; N,17.44 Found: C, 45.27; H, 5.48; N, 17.56 NMR(200 MHz,D₂ O)δ: 1.75(2H,m),1.95(2H,m), 3.02(2H,m), 4.22(2H,t,J=6.8 Hz), 7.58(1H,d,J=7.8 Hz),7.88(1H,d,J=8.8 Hz), 8.32(1H,dd,J=8.8, 7.8 Hz), 8.71(1H,s).

ii) Synthesis of 1,2-dihydro-1-4-(trifluoromethanesulfonamide)butan-1-yl)-1,4,7b-triazacyclopentcd!indene-2-one

To a suspension of 350 mg (1.15 mmol) of 1-4-(amino)butan-1-yl!-1,2-dihydro-1,4,7b-triazacyclopentcd!inden-2-one-dihydrochloride was added 0.64 ml (4.62 mmol) oftriethylamine. The mixture was stirred for 10 minutes at roomtemperature. To the mixture was added 619 mg (1.73 mmol) ofN-phenyltrifluoromethanesulfonimide. The mixture was stirred for 66hours at room teperature. The solvent was distilled off. The residue waspurified by column chromatography(eluent: ethyl acetate) to give 97 mgof the desired compound (23.2%, colorless solid).

NMR(200 MHz,CDCl₃ -DMSO-d₆)δ: 1.70(2H,m), 1.97(2H,m), 3.27(2H,m),4.12(2H,t,J=7.0 Hz), 6.98(1H,d,J=7.4 Hz), 7.65(1H,d,J=8.6 Hz),7.81(1H,dd,J=8.6, 7.4 Hz), 8.33(1H,s), 8.70(1H,br).

iii) Synthesis of 1,2-dihydro-1-4-(trifluoromethanesulfonamide)butan-1-yl)-1,4,7b-triazacyclopentcd!inden-2-one-dihydrochloride

To a suspension of 89 mg (0.25 mmol) of 1,2-dihydro-1-4-(trifluoromethanesulfonamide)butan-1-yl)-1,4,7b-triazacyclopentcd!inden-2-one in 5 ml of methanol was added 0.05 ml of conc. HCl. Thesolvent was distilled off. To the residue was added acetone, and thesolvent was distilled off to give 98 mg of the desired compound (100%,coloress solid).

NMR(200 MHz,DMSO-d₆)δ: 1.59(2H,m), 1.84(2H,m), 3.19(2H,m),4.12(2H,t,J=6.8 Hz), 7.57(1H,d,J=7.6 Hz), 7.84(1H,d,J=8.6 Hz),8.15(1H,dd,J=8.6, 7.6 Hz), 8.84(1H,s), 9.39(1H,brt,J=5.6 Hz).

EXAMPLE 751,2-Dihydro-1-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-1,4,7b-triazacyclopentocd!inden-2-one

i) Synthesis of(1-tert-butoxycarbonylpiperidin-4-ylmethyl)methanesulfonate

To a solution prepared by dissolving 4.31 g (20.0 mM) of1-tert-butoxycarbonyl-4-hydroxymethylpiperidine and 5.54 ml (40.0 mM) oftriethylamine in 50 ml of THF was added 1.86 ml (24.0 mM) ofmethanesulfonyl chloride dropwise at 0° C. After completion of dropwiseaddition, the reaction mixture was stirred at room temperature for 30minutes. After completion of the reaction, the reaction mixture waspoured in 50 ml of iced water and extracted with 50 ml of ethyl acetate.The organic layer was washed with 50 ml of saturated aqueous NaClsolution and dried over anhydrous sodium sulfate (Na₂ SO₄). The solventwas then distilled off under reduced pressure and the residue was driedin vacuo to provide 5.86 g (yield 100%) of the title compound aslight-yellow liquid.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.18-2.32(2H,m), 1.46(9H,s), 1.68-1.82(2H,m),1.82-2.10(1H,m), 2.61-2.82(2H,m), 3.02(3H,s), 4.07(2H,d,J=6.2 Hz),4.09-4.24(2H,m).

ii) Synthesis of1,2-dihydro-1-(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one

A mixture containing 5.68 g (20.0 mM) of(1-tert-butoxycarbonylpiperidin-4-ylmethyl) methanesulfonate, 4.35 g(20.0 mM) of 1,2-dihydro-1,4,7b-triazacyclopent cd!inden-2-one·2NaCl,and 3.58 ml (24.0 mM) of DBU in 50 ml of DMF was heated at 80° C. for 2hours. After completion of the reaction, the reaction mixture was pouredin 50 ml of iced water and extracted with 100 ml of ethyl acetate. Theorganic layer was washed with 50 ml of purified water twice and, then,with 50 ml of saturated aqueous NaCl solution and dried over Na₂ SO₄.The solvent was then distilled off under reduced pressure and theresidue was purified by silica gel column chromatography (eluent: ethylacetate-ethanol=10:1) to provide 3.00 g (yield 42.1%) of the titlecompound as a brown amorphous substance.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.16-2.40(2H,m), 1.45(9H,s), 1.62-1.81(2H,m),2.01-2.24(1H,m), 2.57-2.79(2H,m), 3.97(2H,d,J=7.4 Hz), 4.05-4.29(2H,m),6.86(1H,d,J=7.4 Hz), 7.66(1H,d,J=8.8 Hz), 7.88(1H,dd,J=8.8, 7.4 Hz),8.37(1H,s).

EXAMPLE 76 1,2-Dihydro-1-2-(1-tert-butoxycarbonylpiperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution prepared by dissolving 8.26 g (36.0 mM) of2-(1-tert-butoxycarbonylpiperidin-4-yl)ethanol and 10.0 ml (72.0 mM) oftriethylamine in 50 ml of ether was added 3.34 ml (43.2 mM) ofmethanesulfonyl chloride dropwise at 0° C. After completion of dropwiseaddition, the reaction mixture was stirred at room temperature for 30minutes. After completion of the reaction, the reaction mixture waspoured in 100 ml of iced water and the mixture was extracted with 100 mlof ethyl acetate. The organic layer was washed with 100 ml of saturatedaqueous NaCl solution and dried over anhydrous magnesium sulfate (MgSO₄)and the solvent was distilled off under reduced pressure to recover themesylate as solid. To a solution prepared by dissolving this mesylateand 10.37 g (36.0 mM) of 1,2-dihydro-1,4,7b-triazacyclopentcd!inden-2-one·2NaCl in 25 ml of DMF was added 6.46 ml (43.2 mM) of DBUand the mixture was heated at 80° C. for 2 hours. After completion ofthe reaction, the reaction mixture was poured in iced water and themixture was extracted with 200 ml of ethyl acetate. The organic layerwas washed with 200 ml of purified water 3 times and further with 200 mlof saturated aqueous NaCl solution and dried over MgSO₄. The solvent wasthen distilled off under reduced pressure and the residue was purifiedby silica gel column chromatography (eluent: ethyl acetate) to provide9.10 g (yield 68.2%) of the title compound as light-yellow solid.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.08-1.34(2H,m), 1.46(9H,s), 1.42-1.63(1H,m),1.72-1.91(4H,m), 2.57-2.83(2H,m), 3.98-4.24(4H,m), 6.87(1H,d,J=7.4 Hz),7.66(1H,d,J=8.6 Hz), 7.79(1H,dd,J=8.6, 7.4 Hz), 8.36(1H,s). IR(KBr):1704, 1685, 1624, 1431 cm¹.

EXAMPLE 77 1,2-Dihydro-1-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution prepared by dissolving 5.73 g (25.0 mM) of 2-(1-tert-butoxycarbonyl)piperidin-4-yl!ethanol and 7.0 ml (50.0 mM) oftriethylamine in 50 ml of ether was added 2.3 ml (30.0 mM) ofmethanesulfonyl chloride dropwise at 0° C. After completion of dropwiseaddition, the reaction mixture was stirred at room temperature for 30minutes. After completion of the reaction, the reaction mixture waspoured in 100 ml of iced water and the mixture was extracted with 100 mlof ethyl acetate. The organic layer was washed with 100 ml of saturatedaqueous NaCl solution and dried over MgSO₄ and the solvent was distilledoff under reduced pressure to recover 6.88 g of the mesylate as solid.To 50 ml of DMF was added 6.88 g (22.38 mM) of this mesylate as well as4.46 g (24.62 mM) of 1,2-dihydro-1,4,7b-triazacyclopent cd!inden-2-onesodium salt and the mixture was heated at 100° C. for 1 hour. Aftercompletion of this reaction, the reaction mixture was poured in icedwater and the mixture was extracted with 200 ml of ethyl acetate. Theorganic layer was washed with 200 ml of purified water 3 times andfurther with 200 ml of saturated aqueous NaCl solution and dried overMgSO₄. The solvent was then distilled off under reduced pressure and theresidue was rinsed with ether to provide 5.10 g (yield 55.9%) of thetitle compound as white solid.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.08-1.34(2H,m), 1.46(9H,s), 1.42-1.63(1H,m),1.72-1.91(4H,m), 2.57-2.83(2H,m), 3.98-4.24(4H,m), 6.87(1H,d,J=7.4 Hz),7.66(1H,d,J=8.6 Hz), 7.79(1H,d,J=8.6, 7.4 Hz), 8.36(1H,s). IR(KBr):1704, 1685, 1624, 1431 cm⁻¹.

EXAMPLE 78 1,2-Dihydro-1-3-(1-tert-butoxycarbonylpiperidin-4-yl)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a solution prepared by dissolving 4.87 g (20.0 mM) of1-tert-butoxycarbonyl-4-(3-hydroxypropan-1-yl)-piperidine and 5.54 ml(40.0 mM) of triethylamine in 50 ml of THF was added 1.86 ml (24.0 mM)of methanesulfonyl chloride at 0° C. After completion of dropwiseaddition, the reaction mixture was stirred at room temperature for 30minutes. After completion of this reaction, the reaction mixture waspoured in 50 ml of iced water and extracted with 50 ml of ethyl acetate.The organic layer was washed with 50 ml of saturated NaCl solution anddried over Na₂ SO₄. The solvent was then distilled off under reducedpressure and the residue was dried in vacuo to provide 6.42 g of yellowliquid. To 50 ml of DMF was added 6.42 g (20.0 mM) of3-(1-tert-butoxycarbonylpiperidin-4-yl)propan-1-yl methanesulfonate thusobtained as well as 4.35 g (20.0 mM) of1,2-dihydro-1,4,7b-triazacyclopent cd!inden-2-one·2NaCl and 3.58 ml(24.0 mM) of DBU and the mixture was heated at 80° C. for 2 hours. Aftercompletion of the reaction, the reaction mixture was poured in 50 ml oficed water and extracted with 100 ml of ethyl acetate. The organic layerwas washed with 50 ml of purified water twice and further with 50 ml ofsaturated aqueous NaCl solution and dried over Na₂ SO₄. The solvent wasthen distilled off under reduced pressure and the residue was purifiedby silica gel column chromatography (eluent: ethyl acetate-ethanol=10:1)to provide 3.82 g (yield 49.7%) of the title compound as brown solid.

¹ H-NMR(200 MHz,CDCl₃)δ: 0.98-1.20(2H,m), 1.44(9H,s), 1.32-1.53(2H,m),1.57-1.72(2H,m), 1.79-1.98(3H,m), 2.56-2.75(2H,m), 3.98-4.17(4H,m),6.87(1H,d,J=7.2 Hz), 7.65(1H,d,J=8.6 Hz), 7.78(1H,dd,J=8.6, 7.2 Hz),8.36(1H,s).

EXAMPLE 794,5-Dihydro-4-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one

A solution prepared by dissolving 5.78 g (24.22 mM) of3-carbethoxy-5-chloromethylimidazo 1,2-a!pyridine, 7.78 g (36.33 mM) of1-tert-butoxycarbonyl-4-aminomethylpiperidine, and 6.75 ml (48.44 mM) oftriethylamine in 100 ml of ethanol was refluxed under argon gas for 3hours. After completion of the reaction, the solvent was distilled offunder reduced pressure and the residue was extracted with 100 ml ofchloroform. The organic layer was washed with saturated aqueous NaClsolution and dried over MgSO₄ and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: chloroform-methanol=20:1) to provide 6.50 g(yield 72.4%) of the title compound as yellow liquid.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.30-1.56(2H,m), 1.43(9H,s), 1.79-1.95(2H,m),1.96-2.15(1H,m), 2.58-2.82(2H,m), 3.53-3.71(2H,m), 4.00-4.22(2H,m),5.01(2H,s), 6.72(1H,d,J=6.7 Hz), 7.36(1H,dd,J=9.2, 6.7 Hz),7.54(1H,d,J=9.2 Hz), 8.18(1H,s).

EXAMPLE 80 4,5-Dihydro-4-2-(1-tert-butoxycarbonylpiperidin-4-yl)ethan-1-yl!-3-3H-1,4,8b-triazaacenaphthylen-3-one

In 50 ml of acetonitrile was suspended 6.73 g (20.0 mM) of3-carbethoxy-5-chloromethylimidazo 1,2-a!pyridine sulfate followed byaddition of 5.97 ml (40.0 mM) of DBU at room temperature with stirring.To the resulting solution was added 4.57 g (20.0 mM) of2-(1-tert-butoxycarbonylpiperidin-4-yl)-1-ethylamine as well as 5.54 ml(40.0 mM) of triethylamine and 3.00 g (20.0 mM) of sodium iodide and themixture was stirred at room temperature for 16 hours. After completionof the reaction, the solvent was distilled off under reduced pressureand the residue was extracted with 100 ml of 2-butanone. The organiclayer was washed with 100 ml of saturated aqueous NaCl solution anddried over MgSO₄ and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(eluent: ethyl acetate-ethanol=5:1) to provide 2.88 g (yield 37.5%) ofthe title compound as yellow oil.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.04-1.29(2H,m), 1.45(9H,s), 1.52-1.78(3H,m),1.78-1.84(2H,m), 2.58-2.82(2H,m), 3.54-3.72(2H,m), 3.98-4.20(2H,m),5.00(2H,s), 6.74(1H,d,J=6.6 Hz), 7.35(1H,dd,J=9.2, 6.6 Hz),7.53(1H,d,J=9.2 Hz), 8.17(1H,s).

EXAMPLE 81 4,5-Dihydro-4-3-(1-tert-butoxycarbonylpiperidin-4-yl)propan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one

A solution prepared by dissolving 3.59 g (10.66 mM) of3-carbethoxy-5-chloromethylimidazo 1,2-a!pyridine sulfate, 3.10 g (12.79mM) of 3-(1-tert-butoxycarbonylpiperidin-4-yl)-1-propylamine, and 5.94ml (42.64 mM) of triethylamine in 30 ml of ethanol was refluxed for 5hours. After completion of the reaction, the solvent was distilled offunder reduced pressure and the residue was extracted with 100 ml ofchloroform. The organic layer was washed with 100 ml of saturatedaqueous NaCl solution and dried over MgSO₄ and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (eluent: chloroform-methanol=50:1) to provide 2.55g (yield 62.1%) of the title compound as yellow oil.

¹ H-NMR(200 MHz,CDCl₃)δ: 0.97-1.24(2H,m), 1.25-1.39(3H,m), 1.45(9H,s),1.57-1.81(4H,m), 2.52-2.78(2H,m), 3.57(2H,t,J=7.4 Hz), 3.96-4.18(2H,m),5.01(2H,s), 6.74(1H,d,J=6.0 Hz), 7.33(1H,dd,J=9.2, 7.0 Hz),7.59(1H,d,J=9.2 Hz), 8.18(1H,s). IR(Neat): 1678, 1533, 1161 cm⁻¹.

EXAMPLE 821,2-Dihydro-1-(1-trifluoromethane-sulfonylpiperidin-4-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one

i) Synthesis of1,2-dihydro-1-(piperidin-4-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one dihydrochloride

To a solution of 3.00 g (8.42 mM) of1,2-dihydro-1-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-1,4,7b-triazacyclopentocd!inden-2-one in 50 ml of ethanol was added 10 ml (122 mM) of12N-hydrochloric acid and the mixture was stirred at room temperaturefor 1 hour. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure and the precipitate that formed wasrecovered by filtration. This precipitate was rinsed with small amountsof ethanol and ether to provide 2.30 g (yield 83.0%) of the titlecompound as brown solid.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.42-1.67(2H,m), 1.76-1.95(2H,m),2.05-2.29(1H,m), 2.66-2.93(2H,m), 3.14-3.34(2H,m), 4.04(2H,d,J=7.2 Hz),7.63(1H,d,J=7.6 Hz), 7.87(1H,d,J=8.8 Hz), 8.20(1H,dd,J=8.8, 7.6 Hz),8.92(1H,s).

ii) Synthesis of1,2-dihydro-1-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one

In 20 ml of acetonitrile was suspended 988 mg (3.0 mM) of1,2-dihydro-1-(piperidin-4-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one dihydrochloride followed by addition of 0.9 ml (6.0 mM)of DBU at room temperature and thorough mixing. To the resultingsolution was added 0.83 ml (6.0 mM) of triethylamine, followed byaddition of 1.29 g (3.6 mM) of N-phenyltrifluoromethanesulfonimide, andthe mixture was stirred at room temperature for 16 hours. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure and the residue was extracted with 100 ml of ethyl acetate. Theorganic layer was washed with 100 ml of saturated aqueous NaCl solutionand dried over MgSO₄ and the solvent was then distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate-ethanol=10:1) to provide 890 mg(yield 76.4%) of the title compound as light-yellow crystals.

¹ H-NMR(200 MHz,CDCl₃) δ: 1.39-1.64(2H,m), 1.80-1.96(2H,m),2.08-2.35(1H,m), 2.92-3.13(2H,m), 3.91-4.04(2H,m), 4.01(2H,d,J=7.0 Hz),6.86(1H,d,J=8.6 Hz), 7.80(1H,dd,J=8.6, 6.8 Hz), 8.38(1H,s). IR(KBr):1698, 1507, 1383, 1227 cm⁻¹. Elemental Analysis for C₁₅ H₁₅ N₄ O₃ SF₃ :Calcd.: C, 46.39; H, 3.89; N, 14.43. Found: C, 46.37; H, 3.66; N, 14.19.

EXAMPLE 83 1,2-Dihydro-1-2-(1-(trifluoromethane-sulfonyl)piperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one hydrochloride

i) Synthesis of 1,2-dihydro-1-2-(piperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-onedihydrochloride

To a solution prepared by dissolving 5.30 g (14.13 mM) of 1,2-dihydro-1-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 50 ml of ethanol was added 5.88 ml (71.53 mM) of12N-hydrochloric acid and the mixture was stirred at room temperaturefor 1 hour. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure and the crystals that formed werecollected by filtration and rinsed with small amounts of ethanol andether to provide 3.51 g (yield of 71.5%) of the title compound as whitecrystals.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.32-1.68(3H,m), 1.68-1.84(2H,m),1.84-2.02(2H,m), 2.64-2.93(2H,m), 3.15-3.33(2H,m), 4.14(2H,t,J=7.6 Hz),7.62(1H,d,J=7.6 Hz), 7.86(1H,d,J=8.6 Hz), 8.18(1H,dd,J=8.6, 7.6 Hz),8.90(1H,m), 8.82-9.22(2H,br s,NH₂). IR(KBr): 1714, 1645, 1549 cm⁻¹.

ii) Synthesis of 1,2-dihydro-1-2-(1-(trifluoromethane-sulfonyl)piperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

In 30 ml of acetonitrile was suspended 1.72 g (5.0 mM) of 1,2-dihydro-1-2-(piperidin-4-yl)ethan-1-yl)-1,4,7b-triazacyclopent cd!inden-2-onedihydrochloride, followed by addition of 1.5 ml (10.0 mM) of DBU and 1.4ml (10.0 mM) of triethylamine. Then, 8.93 g (25.0 mM) ofN-phenyltrifluoromethanesulfonimide was added and the mixture wasstirred at room temperature for 16 hours. After completion of thereaction, the solvent was distilled off under reduced pressure and theresidue was extracted with 100 ml of chloroform. The organic layer waswashed with 100 ml of saturated aqueous NaCl solution and dried overMgSO₄ and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent: ethylacetate-ethanol=10:1) to provide 1.54 g (yield 76.3%) of the titlecompound as white solid. Recrystallization of the solid (1.54 g) from 10ml of ethanol gave 1.23 g (recovery rate 80.0%) of prisms.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.24-1.67(3H,m), 1.78-2.06(4H,m),2.92-3.13(2H,m), 3.88-4.04(2H,m), 4.16(2H,t,J=7.0 Hz), 6.87(1H,d,J=7.0Hz), 7.68(1H,d,J=8.6 Hz), 7.80(1H,dd,J=8.6, 7.0 Hz), 8.37(1H,s).IR(KBr): 1689, 1624, 1504 cm⁻¹. Elemental Analysis for C₁₆ H₁₇ N₄ O₃ SF₃: Calcd.: C, 47.76; H, 4.26; N, 13.92. Found: C, 47.57; H, 4.23; N,13.96.

iii) Synthesis of 1,2-dihydro-1-2-(1-trifluoromethanesulfonyl)piperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one hydrochloride

To a solution prepared by dissolving 402 mg (1.0 mM) of 1,2-dihydro-1-2-(1-trifluoromethanesulfonyl)piperidin-4-yl)ethan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 10 ml of 2-propanol was added 0.16 ml (2.0 mM) of12N-hydrochloric acid and the mixture was stirred and concentrated underreduced pressure. The resulting precipitate was recovered by filtrationand rinsed with a small amount of ether to provide 378 mg (yield 86.2%)of the title compound as white crystals.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.12-1.38(2H,m), 1.48-1.79(1H,m),1.79-1.84(2H,m), 1.84-2.02(2H,m), 2.98-3.23(2H,m), 3.69-3.88(2H,m),4.06-4.22(2H,m), 7.61(1H,d,J=7.6 Hz), 7.87(1H,d,J=8.6 Hz),8.18(1H,dd,J=8.6, 7.6 Hz), 8.90(2H,s).

EXAMPLE 84 1,2-Dihydro-1-3-(1-trifluoromethanesulfonylpiperidin-4-yl)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

i) Synthesis of 1,2-dihydro-1-3-(piperidin-4-ylmethyl)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one dihydrochloride

To a solution prepared by dissolving 3.82 g (9.94 mM) of 1,2-dihydro-1-3-(1tert-butoxycarbonylpiperidin-4-yl)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 50 ml of ethanol was added 10 ml (122 mM) of12N-hydrochloric acid and the mixture was stirred at room temperaturefor 1 hour. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure and the resulting precipitate wasrecovered by filtration. The precipitate was rinsed with small amountsof ethanol and ether to provide 2.99 g (yield 84.5%) of the titlecompound as brown solid.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.18-1.44(4H,m), 1.44-1.66(1H,m),1.66-1.91(4H,m), 2.67-2.92(2H,m), 3.09-3.29(2H,m), 4.10(2H,t,J=7.0 Hz),7.68(1H,d,J=7.8 Hz), 7.89(1H,d,J=8.8 Hz), 8.24(1H,dd,J=8.8, 7.8 Hz),9.00(1H,s), 8.87-9.26(2H,m).

ii) Synthesis of 1,2-dihydro-1-3-(1-trifluoromethanesulfonylpiperidin-4-yl)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

In 20 ml of acetonitrile was suspended 1072 mg (3.0 mM) of1,2-dihydro-1- 3-(piperidin-4-yl)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one dihydrochloride followed by addition of 0.9 ml (6.0 mM)of DBU at room temperature and thorough mixing. To the resultingsolution was added 0.83 ml (6.0 mM) of triethylamine. Then, 1.29 g (3.6mM) of N-phenyltrifluoromethanesulfonimide was added and the mixture wasstirred at room temperature for 16 hours. After completion of thereaction, the solvent was distilled off under reduced pressure and theresidue was extracted with 100 ml of ethyl acetate. The organic layerwas washed with 100 ml of saturated aqueous NaCl solution and dried overMgSO₄ and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent: ethylacetate-ethanol=10:1) to provide 870 mg (yield 69.7%) of the titlecompound as light-brown crystals.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.25-1.64(5H,m), 1.64-2.02(4H,m),2.90-3.11(2H,m), 3.84-4.02(2H,m), 4.09(t, 2H, J=7.4 Hz), 6.86 (d, 1H,J=7.0 Hz), 7.66 (1H,d,J=8.8 Hz), 7.78(1H,dd,J=8.8, 7.0 Hz), 8.36(1H,s).IR(KBr): 1701, 1507, 1383, 1228 cm⁻¹. Elemental Analysis for C₁₈ H₁₉ N₄O₃ SF₃ : Calcd.: C, 49.03; H, 4.60; N, 13.45. Found: C, 49.12; H, 4.49;N, 13.43.

EXAMPLE 854,5-Dihydro-4-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride

i) Synthesis of4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onedihydrochloride

To a solution prepared by dissolving 3.71 g (10.0 mM) of4,5-dihydro-4-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onein 50 ml of ethanol was added 4.11 ml of 12N-hydrochloric acid at roomtemperature. This mixture was stirred at room temperature for 1 hour andthe resulting precipitate was recovered by filtration. The precipitatewas rinsed with a small amount of ether and dried in vacuo to provide3.24 g (yield 94.2%) of the title compound as white powders.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.24-1.42(2H,m), 1.76-1.92(2H,m),1.94-2.20(1H,m), 2.64-2.90(2H,m), 3.11-3.30(2H,m), 3.46(2H,d,J=7.2 Hz),5.25(2H,s), 7.42(1H,d,J=7.0 Hz), 7.88(1H,d,J=8.7 Hz), 8.01(1H,dd,J=8.7,7.0 Hz), 8.65(1H,s), 8.95-9.33(2H,m).

ii) Synthesis of4,5-dihydro-4-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one

In 20 ml of THF was suspended 2.06 g (6.0 mM) of4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onedihydrochloride and 3.35 ml (24.0 mM) of triethylamine and 1.51 ml (9.0mM) of trifluoromethanesulfonic anhydride were added in that order at 0°C. The mixture was stirred at room temperature for 1 hour and thesolvent was then distilled off under reduced pressure. The residue wasextracted with 100 ml of chloroform and the organic layer was washedwith 100 ml of saturated aqueous NaCl solution and dried over MgSO₄. Thesolvent was then distilled off under reduced pressure and the residuewas purified by silica gel column chromatography (eluent: ethylacetate-ethanol=10:1) to provide 1.71 g (yield 71.0%) of the titlecompound as light-yellow amorphous substance.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.32-1.58(2H,m), 1.78-1.96(2H,m),1.96-2.17(1H,m), 2.93-3.17(2H,m), 3.51(2H,d,J=7.4 Hz), 3.88-4.07(2H,m),5.03(2H,s), 6.77(1H,d,J=7.0 Hz), 7.36(1H,dd,J=8.8, 7.0 Hz),7.56(1H,d,J=8.8 Hz), 8.19(1H,s).

iii) Synthesis of4,5-dihydro-4-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride

To a solution prepared by dissolving 580 mg (1.44 mM) of4,5-dihydro-4-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onein 10 ml of ethanol was added 0.24 ml (2.88 mM) of 12N-hydrochloric acidwith stirring. The resulting solution was concentrated under reducedpressure and the precipitate was recovered by filtration. Theprecipitate was rinsed with a small amount of ether and dried in vacuoto provide 480 mg (yield 80.0%) of the title compound as white solid.

¹ H-NMR(200MHz,DMSO-d₆)δ: 1.24-1.41(2H,m), 1.75-1.94(2H,m),1.96-2.22(2H,m), 3.04-3.26(2H,m), 3.48(2H,d,J=7.4 Hz), 3.73-3.91(2H,m),5.25(2H,s), 7.38(1H,d,J=7.0 Hz), 7.83(1H,d,J=8.6 Hz), 7.95(1H,dd,J=8.6,7.0 Hz), 8.59(1H,s).

EXAMPLE 86 4,5-Dihydro-4-2-(1-trifluoromethanesulfonylpiperidin-4-yl)ethan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one

i) Synthesis of 4,5-dihydro-4-2-(piperidin-4-yl)ethan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onedihydrochloride

To a solution prepared by dissolving 2.88 g (7.49 mM) of 4,5-dihydro-4-2-(1-tert-butoxycarbonylpiperidin-4-yl)ethan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onein 30 ml of ethanol was added 6.25 ml (74.9 mM) of 12N-hydrochloric acidand the mixture was stirred at room temperature for 1 hour. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure and the precipitate was recovered by filtration. Theprecipitate was rinsed with small amounts of ethanol and ether toprovide 2.13 g (yield 79.8%) of the title compound as light-yellowcrystals.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.29-1.76(5H,m), 1.78-1.98(2H,m),2.64-2.91(2H,m), 3.12-3.31(2H,m), 3.47-3.66(2H,m), 5.27(2H,s),7.43(1H,d,J=7.0 Hz), 7.86(1H,d,J=8.8 Hz), 8.00(1H,dd,J=8.8, 7.0 Hz),8.64(1H,s), 8.93-9.31(2H,m).

ii) Synthesis of 4,5-dihydro-4-2-(1-trifluoromethanesulfonylpiperidin-4-yl)ethan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one

In 15 ml of acetonitrile was suspended 713 mg (2.0 mM) of 4,5-dihydro-4-2-(piperidin-4-yl)ethan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride followed by addition of 0.6 ml (4.0 mM) of DBU at roomtemperature with stirring. To the resulting solution was added 0.83 ml(6.0 mM) of triethylamine as well as 0.37 ml (2.2 mM) oftrifluoromethanesulfonic anhydride at 0° C. and the mixture was stirredat room temperature for 1 hour. After completion of the reaction, thesolvent was distilled off under reduced pressure and the residue wasextracted with 50 ml of 2-butanone. The organic layer was washed with 50ml of saturated aqueous NaCl solution and dried over MgSO₄ and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: ethylacetate-ethanol=9:1) to provide 434 mg (yield 35.0%) of the titlecompound as light-yellow amorphous substance.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.26-1.48(2H,m), 1.48-1.75(3H,m),1.88-2.04(2H,m), 2.84-3.02(2H,m), 3.65(2H,t,J=6.8 Hz), 3.88-4.04(2H,m),5.04(2H,s), 6.81(1H,d,J=6.2 Hz), 7.38(1H,dd,J=9.2, 6.2 Hz),7.54(1H,d,J=9.2 Hz), 8.14(1H,s). IR(KBr): 1732, 1709, 1633, 1227 cm⁻¹.

EXAMPLE 87 4,5-Dihydro-4-3-(1-trifluoromethanesulfonylpiperidin-4-yl)propan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride

i) Synthesis of 4,5-dihydro-4-3-(piperidin-4-yl)propan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onedihydrochloride

To a solution prepared by dissolving 2.12 g (5.51 mM) of 4,5-dihydro-4-3-(1-tert-butoxycarbonylpiperidin-4-yl)propan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onein 30 ml of ethanol was added 1.40 ml of 12N-hydrochloric acid and themixture was stirred at room temperature for 1 hour. After completion ofthe reaction, the solvent was distilled off under reduced pressure. Tothe residue was added 5 ml of ethanol and 5 ml of ether and theresulting precipitate was recovered by filtration. The precipitate wasrinsed with small amounts of ethanol and ether to provide 1.87 g (yield91.2%) of the title compound as light-yellow crystals.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.17-1.51(4H,m), 1.51-1.72(3H,m),1.71-1.89(2H,m), 2.67-2.94(2H,m), 3.09-3.31(2H,m), 3.36-3.61(2H,m),5.29(2H,s), 7.47(1H,d,J=6.4 Hz), 7.89(1H,d,J=9.0 Hz), 8.02(1H,d,J=7.4Hz), 8.67(1H,s), 8.82-9.28(2H,m,NH). IR(KBr): 1653, 1599, 1443 cm⁻¹.

ii) Synthesis of 4,5-dihydro-4-3-(1-trifluoromethanesulfonylpiperidin-4-yl)propan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one

In 20 ml of acetonitrile was suspended 1.37 g (3.69 mM) of4,5-dihydro-4-3-(piperidin-4-yl)propan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride followed by addition of 1.1 ml (7.38 mM) of DBU at roomtemperature with stirring. To the resulting solution was added 1.0 ml(7.38 mM) of triethylamine as well as 6.59 g (18.45 mM) ofN-phenyltrifluoromethanesulfonimide and the mixture was stirred at roomtemperature for 16 hour. After completion of the reaction, the solventwas distilled off under reduced pressure and the residue was extractedwith 100 ml of chloroform. The organic layer was washed with 100 ml ofsaturated aqueous NaCl solution and dried over MgSO₄ and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform-methanol=50:1) to provide1.08 g (yield 68.3%) of the title compound as light-yellow solid.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.16-1.61(4H,m), 1.61-1.91(5H,m),2.92-3.11(2H,m), 3.58(2H,t,J=7.6 Hz), 3.87-4.03(2H,m), 5.01(2H,s),6.75(1H,d,J=7.0Hz), 7.36(1H,dd,J=9.0, 7.0 Hz), 7.54(1H,d,J=9.0 Hz),8.18(1H,s). IR(KBr): 1647, 1543, 1387, 1182 cm⁻¹.

iii) Synthesis of 4,5-dihydro-4-3-(1-trifluoromethanesulfonylpiperidin-4-yl)propan-1-yl!-3H-1,4,8b-triazaacenaphthylene-3-onehydrochloride

To a solution prepared by dissolving 300 mg (0.70 mM) of 4,5-dihydro-4-3-(1-trifluoromethanesulfonyl-piperidin-4-yl)propan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-onein 10 ml of ethanol was added 0.12 ml (1.4 mM) of 12N hydrochloric acidat room temperature. After stirring, the solvent was distilled off underreduced pressure and 10 ml of 2-propanol was added to the residue. Theprecipitate that formed was recovered by filtration and rinsed with asmall amount of ether to provide 265 mg (yield 81.1%) of the titlecompound as light-yellow solid.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.07-1.41(4H,m), 1.43-1.74(3H,m),1.74-1.89(2H,m), 3.04-3.25(2H,m), 3.40-3.91(4H,m), 5.25(2H,s),7.40(1H,d,J=7.2 Hz), 7.83(1H,d,J=9.0 Hz), 7.96(1H,dd,J=9.0, 7.2 Hz),8.60(1H,s). IR(KBr): 1666, 1552, 1375, 1184 cm⁻¹. m.p. 172-174° C.Elemental Analysis for C₁₈ H₂₂ N₄ O₃ SClF₃ ·H₂ O: Calcd.: C, 44.58; H,4.99; N, 11.55. Found: C, 44.31; H, 4.65; N, 11.17.

EXAMPLE 884,5-Dihydro-4-(1-trifluoroacetylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride

i) Synthesis of4,5-dihydro-4-(1-trifluoroacetyl-piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one

In 20 ml of acetonitrile was suspended 687 mg (2.0 mM) of4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onedihydrochloride followed by addition of 2.23 ml (16.0 mM) oftriethylamine and 1.41 ml (10.0 mM) of trifluoroacetic anhydride in theorder mentioned. This mixture was stirred at room temperature for 1 hourand the solvent was then distilled off under reduced pressure. Theresidue was extracted with 50 ml of chloroform and the organic layer waswashed with 50 ml of saturated aqueous NaCl solution and dried overMgSO₄. The solvent was then distilled off under reduced pressure and theresidue was purified by silica gel column chromatography (eluent: ethylacetate-ethanol=10:1) to provide 540 mg (yield 73.7%) of the titlecompound as light-yellow amorphous substance.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.13-1.40(2H,m), 1.82-2.00(2H,m),2.05-2.26(2H,m), 2.66-2.85(1H,m), 3.02-3.24(1H,m), 3.30-3.42(1H,m),3.54-3.68(1H,m), 4.00-4.11(1H,m), 4.45-4.60(1H,m), 5.00(1H,s),6.75(1H,d,J=6.8 Hz), 7.35(1H,dd,J=8.8, 6.8 Hz), 7.57(1H,d,J=8.8 Hz),8.20(1H,s).

ii) Synthesis of4,5-dihydro-4-(1-trifluoroacetylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride

To a solution prepared by dissolving 540 mg (1.47 mM) of4,5-dihydro-4-(1-trifluoroacetylpiperidin-4-yl-methyl)-3H-1,4,8b-triazaacenaphthylen-3-onein 10 ml of ethanol was added 0.24 ml (2.94 mM) of 12N-hydrochloric acidwith stirring. The resulting solution was concentrated under reducedpressure and the precipitate that formed was recovered by filtration.The precipitate was rinsed with a small amount of ether and dried invacuo to provide 330 mg (yield 55.7%) of the title compound as whitesolid.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.26-1.42(2H,m), 1.72-1.91(2H,m),1.93-2.20(1H,m), 3.03-3.26(2H,m), 3.46(2H,d,J=7.0 Hz), 3.73-3.88(2H,m),5.22(2H,s), 7.38(1H,d,J=6.8 Hz), 7.86(1H,d,J=8.8 Hz), 7.95(1H,dd,J=8.8,6.8 Hz), 8.61(1H,s).

EXAMPLE 89 4,5-Dihydro-4-2-(1-trifluoroacetylpiperidin-4-yl)ethan-1-yl!-3H-1,4,8b-triazaacenaphthylen-3-one

In 15 ml of acetonitrile was suspended 713 mg (2.0 mM) of 4-2-(piperidin-4-yl)ethan-1-yl!-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride followed by addition of 0.6 ml (4.0 mM) of DBU at roomtemperature with stirring. To the resulting solution was added 0.83 ml(6.0 mM) of triethylamine as well as 0.31 ml (2.2 mM) of trifluoroaceticanhydride at 0° C. and the mixture was stirred at room temperature for 1hour. After completion of the reaction, the solvent was distilled offunder reduced pressure and the residue was extracted with 50 ml of2-butanone. The organic layer was washed with 50 ml of saturated aqueousNaCl solution and dried over MgSO₄ and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate-ethanol=9:1) to provide 455 mg(yield 59.8%) of the title compound as light yellow solid.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.13-1.41(2H,m), 1.56-1.71(3H,m),1.85-2.07(2H,m), 2.66-2.85(1H,m), 3.01-3.22(1H,m), 3.65(2H,t,J=7.0 Hz),3.93-4.12(1H,m), 4.46-4.62(1H,m), 5.01(2H,s), 6.76(1H,d,J=7.0 Hz),7.34(1H,dd,J=7.0, 9.2 Hz), 7.56(1H,d,J=9.2 Hz), 8.19(1H,s). IR(KBr):1683, 1657, 1180, 1146 cm⁻¹.

EXAMPLE 904,5-Dihydro-4-(1-pentafluoropropionylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride

i) Synthesis of4,5-dihydro-4-(1-pentafluoropropionylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one

In 10 ml of acetonitrile was suspended 687 mg (2.0 mM) of4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onedihydrochloride, followed by addition of 2.23 ml (16.0 mM) oftriethylamine and 1.97 ml (10.0 mM) of pentafluoropropionic anhydride inthe order mentioned. This mixture was stirred at room temperature for 1hour and the solvent was then distilled off under reduced pressure. Theresidue was extracted with 50 ml of chloroform and the organic layer waswashed with 50 ml of saturated aqueous NaCl solution and dried overMgSO₄. The solvent was distilled off under reduced pressure and theresidue was purified by silica gel column chromatography (eluent: ethylacetate-ethanol=10:1) to provide 526 mg (yield 63.2%) of the titlecompound as light-yellow amorphous substance.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.22-1.53(2H,m), 1.80-1.97(2H,m),2.05-2.27(1H,m), 2.71-2.89(1H,m), 3.06-3.23(1H,m), 3.31-3.46(1H,m),3.52-3.68(1H,m), 4.05-4.23(1H,m), 4.46-4.62(1H,m), 5.04(2H,s),6.77(1H,d,J=6.8 Hz), 7.36(1H,dd,J=9.2, 6.8 Hz), 7.57(1H,d,J=9.2 Hz),8.20(1H,s).

ii) Synthesis of4,5-dihydro-4-(1-pentafluoropropionylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onehydrochloride

To a solution of 526 mg (1.26 mM) of4,5-dihydro-4-(1-pentafluoropropionylpiperidin-3-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-onein 10 ml of ethanol was added 0.20 ml (2.52 mM) of 12N-hydrochloric acidwith stirring. The resulting solution was concentrated under reducedpressure and the precipitate that formed was recovered by filtration.This precipitate was rinsed with a small amount of ether and dried invacuo to provide 430 mg (yield 75.4%) of the title compound as whitesolid.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.23-1.40(2H,m), 1.73-1.93(2H,m),1.95-2.22(1H,m), 3.02-3.25(2H,m), 3.46(2H,d,J=7.2 Hz), 3.72-3.89(2H,m),5.24(2H,s), 7.36(1H,d,J=7.0 Hz), 7.85(1H,d,J=8.8 Hz), 7.96(1H,dd,J=8.8,7.0 Hz), 8.60(1H,s).

REFERENCE EXAMPLE 1 5-Ethoxycarbonyl-3-trichloroacetylimidazo1,2-a!pyridine

To a solution of 25.22 g (0.133 mol) of 5-ethoxycarbonylimidazo1,2-a!pyridine and 48.60 g (0.398 mol) of 4-dimethylaminopyridine wasadded dropwise 72.33 g (0.398 mol) of trichloroacetyl chloride. Themixture was heated for 63 hours under reflux. After cooling, thereaction mixture was washed with an aqueous solution of sodiumhydrogencarbonate, dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified by column chromatography(eluent: ethyl acetate/n-hexane=1:1) to give 33.10 g of the desiredcompound (77.4%, yellow solid).

¹ NMR(200 MHz,CDCl₃) δ: 1.40(3H,J=7.2 Hz), 4.46(2H,q,J=7.2 Hz),7.57-7.72(2H,m), 7.98(1H,dd,J=8.0,2.0 Hz), 8.84(1H,s).

REFERENCE EXAMPLE 2 5-Ethoxycarbonyl-2-methyl-3-trichloroacetylimidazo1,2-a!pyridine

To a solution of 8.03 g (39.3 mmol) of 5-ethoxycarbonyl-2-methylimidazo1,2-a!pyridine and 14.41 g (118 mmol) of 4-dimethylaminopyridine in 80ml of chloroform was added dropwise 21.45 g (118 mmol) oftrichloroacetyl chloride. The mixture was heated for 15 hours underreflux. After cooling, the reaction mixture was washed with an aqueoussolution of sodium hydrogencarbonate, drid over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purified bycolumn chromatography (eluent: ethyl acetate/n-hexane=2:1) to give 8.29g of the desired compound (60.3%, pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.45(3H,J=7.2 Hz), 2.65(3H,s), 4.49(2H,q,J=7.2Hz), 7.40(1H,dd,J=8.8,7.2 Hz), 7.77(1H,dd,J=7.2,1.2 Hz),7.84(1H,dd,J=8.8,1.2 Hz).

REFERENCE EXAMPLE 3 5-Amino-3-ethoxycarbonyl-2-methylimidazo1,2-a!pyridine-hydrochloride

To a suspension of 43.7 g (0.40 mol) of 2,6-diaminopyridine in 400 ml ofethanol was added 131.7 g (0.8 mol) of ethyl 2-chloroacetoacetate. Themixture was heated for 18 hours under reflux. After cooling, theresulting crystals was collected by filtration, washed with ethanol andether successively to give 58.4 g of the desired compound (57.1%, paleyellow crystals).

NMR(200 MHz,D₂ O) δ: 1.41(3H,t,J=7.2 Hz), 2.61(3H,s), 4.42(2H,q,J=7.2Hz), 6.53(1H,d,J=8.2 Hz), 6.87(1H,d,J=8.2 Hz), 7.68(1H,t,J=8.2 Hz).

REFERENCE EXAMPLE 4 1,2-Dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 4.8 g (120 mmol) of sodium hydride (60% dispersion inoil) in 60 ml of DMF was added 10.23 g (40 mmol) of5-amino-3-ethoxycarbonyl-2-methylimidazo 1,2-a!pyridine-hydrochloridewith small portions. The mixture was stirred for 0.5 hour, then for 0.5hour at 100° C., which was left standing for cooling. To the reactionmixture was added 60 ml of water. The mixture was washed withchloroform, to which was added, while stirring at room temperature,conc. HCl to make the pH of the solution 8. The resulting precipitatewas collected by filtration, washed with water and ether, successivelyto give 5.97 g of the desired compound (86.1%, pale brown solid).

NMR(200 MHZ,DMSO-d₆) δ: 2.65(3H,s), 6.94(1H,d,J=7.4 Hz), 7.48(1H,d,J=8.6Hz), 7.76(1H,dd,J=8.6,7.4 Hz), 12.1(1H,br).

REFERENCE EXAMPLE 5 1,2-Dihydro-3-methyl-1-5-(phthalimido)pentan-1-yl)-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 5.20 g (30 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-one in 60 ml ofDMF was added, while stirring under ice-cooling, 1.44 g (36 mmol) of 60%sodium hydride (dispersion in oil). The mixture was stirred for 15minutes at the same temperature. To the reaction mixture was added asolution of 8.89 g (30 mmol) of N-(5-bromopentyl)phthalimide in DMF (20ml). The mixture was stirred for 1.5 hour at 110° C. After cooling, thereaction mixture was poured into water, extracted with ethyl acetate.The extract solution was washed with water, dried over anhydrousmagnesium sulfate and concentrated. The concentrate was purified bycolumn chromatography (eluent: ethyl acetate/ethanol=10:1) to afford6.93 g of the desired compound (59.4%, pale brown solid).

¹ NMR(200 MHz,CDCl₃) δ: 1.46(2H,m), 1.76(2H,m), 1.91(2H,m), 2.80(3H,s),3.68(2H,t,J=7.0 Hz), 4.05(2H,t,J=7.2 Hz), 6.83(1H,d,J=7.4 Hz),7.58(1H,d,J=8.6 Hz), 7.70(1H,dd,J=8.6,7.4 Hz), 7.66-7.85(4H,m).

REFERENCE EXAMPLE 6 1,2-Dihydro-3-methyl-1-6-(phthalimido)hexan-1-yl-1,4,7b-triazacyclopent cd!inden-2-one

To a suspension of 5.20 g (30 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-one in 60 ml ofDMF was added, while stirring under ice-cooling, 1.44 g (36 mmol) of 60%sodium hydride (dispersion in oil). The mixture was stirred for 15minutes at the same temperature. To the reaction mixture was added a DMFsolution (20 ml) of 9.31 g (30 mmol) of N-(6-bromohexyl)phthalimide. Themixture was stirred for 1.5 hour at 110° C. After cooling, the reactionmixture was poured into water, which was extracted with ethyl acetate.The extract was washed with water, dried over anhydrous magnesiumsulfate, and concentrated. The concentrate was purified by columnchromatography (eluent: ethyl acetate/ethanol=10:1) to give 3.47 g ofthe desired compound (28.7%, pale brown solid).

NMR(200 MHz,CDCl₃) δ: 1.33-1.56(4H,m), 1.68(2H,m), 1.85(2H,m),2.82(3H,s), 3.67(2H,t,J=7.2 Hz), 4.04(2H,t,J=7.2 Hz), 6.78(1H,d,J=7.4Hz), 7.47(1H,d,J=8.6 Hz), 7.69(1H,dd,J=8.6,7.4 Hz), 7.67-7.76(2H,m),7.78-7.88(2H,m).

REFERENCE EXAMPLE 7 1,2-Dihydro-3-methyl-1-3-(phthalimido)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 8.66 g (50 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-one in 100 ml ofDMF was added, while stirring under ice-cooling, 2.20 g (55 mmol) of 60%sodium hydride (dispersion in oil). The mixture was stirred for 20minutes at the same temperature. To the reaction mixture was added 13.14g (50 mmol) of N-(3-bromopropyl)phthalimide. The mixture was stirred for7 hours at 100° C. After cooling, the reaction mixture was poured intowater, which was subjected to extraction with chloroform. The extractwas dried over anhydrous magnesium sulfate, and, the solvent was thendistilled off. The residue was crystallized from methylenechloride--ethanol to give 5.72 g of the desired compound (31.7%, palebrown solid substance).

NMR(200 MHz,CDCl₃) δ: 2.29(2H,m), 2.81(3H,s), 3.85(2H,t,J=7.0 Hz),4.16(2H,t,J=7.2 Hz), 6.86(1H,d,J=7.4 Hz), 7.48(1H,d,J=8.6 Hz),7.79(1H,dd,J=8.6,7.4 Hz), 7.66-7.76(4H,m).

REFERENCE EXAMPLE 8 1,2-Dihydro-3-methyl-1-4-(phthalimido)butan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one

To a suspension of 8.66 g (50 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-one in 100 ml ofDMF was added, while stirring under ice-cooling, 2.20 g (55 mmol) of 60%sodium hydride (dispersion in oil). The mixture was stirred for 15minutes at the same temperature. To the reaction mixture was added 14.10g (50 mmol) of phthalimide, which was stirred for 6 hours at 100° C.After cooling, the reaction mixture was then poured into water,extracted with chloroform. The extract solution was dried over anhydrousmagnesium sulfate, the solvent was distilled off. The residue waspurified by column chromatography (eluent: ethyl acetate) to give 11.43g of the desired compound (61.1%, pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.70-2.00(4H,m), 2.81(3H,s), 3.76(2H,t,J=6.6 Hz),4.12(2H,t,J=6.8 Hz), 6.85(1H,d,J=7.6 Hz), 7.47(1H,d,J=8.6 Hz),7.69(1H,dd,J=8.6,7.6 Hz), 7.65-7.88(4H,m).

REFERENCE EXAMPLE 9 1-5-(Amino)pentan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 6.26 g (16.1 mmol) of 1,2-dihydro-3-methyl-1-5-(phthalimido)pentan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one in 120ml of ethanol was added 2.42 g (48.3 mmol) of hydrazine monohydrate. Themixture was heated for two hours under reflux. After cooling, theresulting precipitates were filtered off. The filtrate was concentratedto give the residue, water was added, extracted with chloroform (threetimes). The extract was dried over anhydrous magnesium sulfate. Thesolvent was distilled off to give 3.31 g of the desired compound (79.6%,pale yellow solid substance).

NMR(200 MHz,CDCl₃) δ: 1.34-1.60(6H,m), 1.88(2H,m), 2.70(2H,t,J=6.8 Hz),2.83(3H,s), 4.07(2H,t,J=7.2 Hz), 6.79(1H,d,J=7.4 Hz), 7.48(1H ,d,J=8.6Hz), 7.70(1H,d,J=8.6,7.4 Hz).

REFERENCE EXAMPLE 10 1-6-(Amino)hexan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 2.94 g (7.31 mmol) of 1,2-dihydro-3-methyl-1-6-(phthalimido)hexan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one in 80 mlof ethanol was added 1.10 g (22.0 mmol) of hydrazine.monohydrate. Themixture was heated for 2 hours under reflux. After cooling, theresulting precipitates were filtered off. The filtrate was concentratedto give the residue, water was added, extracted with chloroform (threetimes). The extract was dried over anhydrous magnesium sulfate, then thesolvent was distilled off to give 1.50 g of the desired compound (75.4%,pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.25-1.52(8H,m), 1.86(2H,m), 2.68(2H,m),2.83(3H,s), 4.06(2H,t,J=7.2 Hz), 6.79(1H,d,J=7.4 Hz), 7.48(1H,d,J=8.6Hz), 7.70(1H,dd,J=8.6,7.4 Hz).

REFERENCE EXAMPLE 11 1-3-(Amino)propan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 3.47 g (9.63 mmol) of 1,2-dihydro-3-methyl-1-3-(phthalimido)propan-1-yl!-1,4,7b-triazacyclopent cd!inden-2-one in 70ml of ethanol was added 1.45 g (29.0 mmol) of hydrazine monohydrate. Themixture was heated for 2 hours under reflux. After cooling, and theresulting precipitates were filtered off. The filtrate was concentratedto give the residue, water was added, extracted with chloroform (threetimes). The extract was dried over anhydrous magnesium sulfate, then thesolvent was distilled off to give 1.68 g of the desired compound (75.8%,pale yellow solid substance).

NMR(200 MHz,CDCl₃) δ: 1.48(2H,br), 1.98(2H,m), 2.78(2H,t,J=6.6 Hz),2.83(3H,s), 4.18(2H,t,J=6.8 Hz), 6.86(1H,d,J=7.4 Hz), 7.49(1H,d,J=8.8Hz), 7.70(1H,dd,J=8.8,7.4 Hz).

REFERENCE EXAMPLE 12 1-4-(Amino)butan-1-yl!-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 5.99 g (16.0 mmol) of 1,2-dihydro-3-methyl-1-4-(phthalimido)butan-1-yl!-1,4,7bbtriazacyclopentcd!inden-2-one in 150ml of ethanol was added 2.40 g (48.0 mmol) of hydrazine monohydrate. Themixture was heated for one hour under reflux. After cooling, and theresulting precipitates were filtered off. The filtrate was concentratedto give the residue, water was water, extracted with chloroform (threetimes). The extract solution was dried over anhydrous magnesium sulfate.The solvent was distilled off to give 3.17 g of the desired compound(81.1%, pale yellow solid).

NMR(200 MHz,CDCl₃) δ: 1.37(2H,br), 1.56(2H,m), 1.91(2H,m),2.77(2H,t,J=7.0 Hz), 2.83(3H,s), 4.09(2H,t,J=7.0 Hz), 6.81(1H,d,J=7.4Hz), 7.49(1H,d,J=8.8 Hz), 7.71(1H,dd,J=8.8,7.4 Hz).

REFERENCE EXAMPLE 13 1,2-Dihydro-3-methyl-1,4,7b-triazacyclopentocd!indene-2-thione

A mixture of 8.66 g (50 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-one and 24.27 g(60 mmol) of a Lawesson's reagent in 200 ml of pyridine was stirred for5 hours at 100° C. After cooling, the resulting precipitates werecollected by filtration, washed with pyridine and ether in that order togive 6.90 g of the desired compound (72.9%, brown solid substance). Thiscompound was used, in the subsequent reaction without furtherpurification.

NMR(200 MHz,DMSO-d₆) δ: 2.75(3H,s), 7.24(1H,d,J=7.6 Hz), 7.68(1H,d,J=8.4Hz), 7.93(1H,dd,J=8.4,7.6 Hz).

REFERENCE EXAMPLE 14 3-Methyl-2-4-(phthalimido)butan-1-ylthio!-1,4,7b-triazacyclopent cd!indene

A mixture of 5.68 g (30 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!indene-2-thione, 8.47 g(30 mmol) of N-(4-bromobutyl)phthalimide and 6.27 ml (45 mmol) oftriethylamine in 150 ml of DMF was stirred for 2 hours at 100° C. Aftercooling, the reaction mixture was poured into water, extracted withethyl acetate. The extract solution was washed with water, dried overanhydrous magnesium sulfate and concentrated. The residue wascrystallized from chloroform-ethanol to give 7.39 g of the desiredcompound (63.1%, pale brown solid)

NMR(200 MHz,CDCl₃) δ: 1.96(4H,m), 2.89(3H,s), 3.56(2H,m), 3.77(2H,m),7.62-7.75(4H,m), 7.76-7.85(2H,m), 7.92(1H,m).

REFERENCE EXAMPLE 15 2-4-(Amino)butan-1-ylthio!-3-methyl-1,4,7b-triazacyclopent cd!indene

To a suspension of 3.90 g (10.0 mmol) of 3-methyl-4-(phthalimido)butan-1-ylthio!-1,4,7b-triazacyclopent cd!indene in 70 mlof ethanol was added 1.50 g (30.0 mmol) of hydrazine monohydrate. Themixture was heated for 2 hours under reflux. After cooling the resultingprecipitates were filtered off. The filtrate was concentrated to givethe residue, water was added, extracted with chloroform. The extract wasdried over anhydrous magnesium sulfate, then the solvent was distilledoff to give 1.89 g of the desired compound (72.7%, pale brown solid)

NMR(200 MHz,CDCl₃) δ: 1.51(2H,br), 1.69(2H,m), 1.96(2H,m),2.79(2H,t,J=6.8 Hz), 2.90(3H,s), 3.54(2H,t,J=7.2 Hz), 7.66(1H,d,J=8.0Hz), 7.71(1H,d,J=7.8 Hz), 7.93(1H,dd,J=8.0,7.8 Hz).

REFERENCE EXAMPLE 16 4-4-(Amino)phenylmethyl!-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 1.47 g (12.0 mmol) of 4-aminobenzylamine and 1.68 g(13.0 mmol) of N,N-diisopropylethylamine was added a solution of 3.50 g(10.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridinein 10 ml of acetonitrile. The mixture was stirred for 7 hours at roomtemperature. The resulting precipitate was collected by filtration,washed with acetonitrile and dried to afford 2.586 g of the desiredcompound (86.7%, a yellow crystals).

Elemental Analysis Calcd for C₁₆ H₁₂ N₄ O₂ : Calcd.: C, 65.75; H, 4.14;N, 19.17 Found: C, 65.53; H, 3.94; N, 19.19 NMR(200 MHz,DMSO-d₆)8:4.99(2H,br), 5.03(2H,s), 6.47(2H,d,J=8.4 Hz), 7.10(2H,d,J=8.4 Hz),7.89(1H,dd,J=8.8, 7.4 Hz), 8.12(1H,dd,J=7.4, 1.0 Hz), 8.28(1H,dd,J=8.8,1.0 Hz), 8.66(1H,s).

REFERENCE EXAMPLE 17 4- 2-4-(Amino)phenyl!ethan-1-yl!-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 1.63 g (12.0 mmol) of 2- 4-(amino)phenyl!ethylamine and1.68 g (13 mmol) of N,N-diisopropylethylamine in 40 ml of acetonitrilewas added a solution of 3.50 g (10.0 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine in 10 ml ofacetonitrile. The mixture was stirred for one hour at room temperature.The resulting crystalline precipitates were collected by filtration,washed with acetonitrile and dried to afford 1.03 g of the desiredcompound (33.6%, a yellow crystals). The filtrate was concentrated. Theresidne was crystallized from acetonitrile-methylene chloride.Crystalline precipitatse were collected by filtration, washed withacetonitrile to afford 1.60 g of the desired compound (52.1%, a yellowcrystals).

NMR(200 MHz,DMSO-d₆)δ: 2.71(2H,m), 4.12(2H,m), 4.89(2H,br), 6.51(2H,m),6.92(2H,m), 7.90(1H,dd,J=8.8, 7.4 Hz), 8.13(1H,dd,J=7.4, 0.8 Hz),8.29(1H,dd,J=8.8, 0.8 Hz), 8.66(1H,s).

REFERENCE EXAMPLE 18 3-Methyl-2-5-(phthalimido)pentan-1-ylthio!-1,4,7b-triazacyclopent cd!inden

To a suspension of 2.03 g (10.7 mmol) of1,2-dihydro-3-methyl-1,4,7b-triazacyclopent cd!inden-2-thione in 50 mlof N,N-dimethylformamide were added 3.18 g (10.7 mmol) ofN-(5-bromopentyl)phthalimide and 2.24 ml (16.1 mmol) of triethylamine.The mixture was stirred for two hours at 100° C. After cooling, theresulting precipitates were collected by filtration, washed withN,N-dimethylformamide, ethanol, and diethylether, successively, dried toafford 3.44 g of the desired compound (79.3%, a pale brown solid).

NMR(200 MHz,CDCl₃)δ: 1.48-1.88(4H,m), 1.96(2H,m), 2.89(3H,s),3.51(2H,t,J=7.2 Hz), 3.73(2H,t,J=7.0 Hz), 7.62-7.87(6H,m),7.94(1H,dd,J=8.0, 7.8 Hz).

REFERENCE EXAMPLE 19 3-Methyl-2-5-(amino)pentan-1-ylthio!-1,4,7b-triazacyclopent cd!indene

To a suspension of 2.50 g (6.2 mmol) of 3-methyl-2-5-(phthalimido)pentan-1-ylthio!-1,4,7b-triazacyclopent cd!indene in 50ml of ethanol was added 928 mg (18.5 mmol) of hydrazinemonohydrate. Themixture was heated for two hours under reflux. After cooling, theresulting precipitates were collected by filtration and washed withethanol. The filtrate and washing were combined and concentrated to givethe residue. Water was added, extracted with methylene chloride, driedover anhydrous magnesium sulfate. The solvent was distilled off toafford 1.197 g of the desired compound (70.6%, a greenish brown solid).

NMR(200 MHz,CDC₃)δ: 1.44(2H,br), 1.56(4H,m), 1.93(2H,m), 2.73(2H,m),2.91(3H,s), 3.54(2H,t,J=7.2 Hz), 7.67(1H,d,J=7.8 Hz), 7.73(1H,d,J=8.0Hz), 7.94(1H,dd,J=8.0, 7.8 Hz).

REFERENCE EXAMPLE 20 3-Dimethylaminomethyl-5-ethoxycarbonylimidazo1,2-a!pyridine

To a solution of 1.90 g (10.0 mmol) of 5-ethoxycarbonylimidazo1,2-a!pyridine in 40 ml of acetonitrile was added 2.41 g (13.0 mmol) ofN,N-dimethylmethyleneammonium iodide. The mixture was heated for twohours under reflux. The solvent was distilled off. To the residue wasadded methylene chloride. The mixture was washed with an aqueoussolution of sodium thiosulfate and an aqueous solution of sodiumhydrogencarbonate, successively, dried over anhydrous magnesium sulfate.The solvent was distilled off, and the residue was purified by columnchromatography (eluent: ethyl acetate) to afford 1.496 g of the desiredcompound (60.6%, a pale yellow solid). This product was recrystallizedfrom ethyl acetate to afford the desired compound (colorless crystals),m.p.117.0-118.0° C.

Elemental Analysis Calcd for C₁₃ H₁₇ N₃ O₂ : Calcd.: C, 63.14; H, 6.93;N, 16.99 Found: C, 63.09; H, 6.68; N, 16.94 NMR(200 MHz,CDCl₃)δ:1.45(3H,t,J=7.2 Hz), 1.96(6H,s), 3.72(2H,s), 4.45(2H,q,J=7.2 Hz),7.20(1H,dd,J=8.8, 7.0 Hz), 7.28(1H,dd,J=7.0, 1.6 Hz), 7.59(1H,s),7.78(1H,dd,J=8.8, 1.6 Hz). IR(KBr): 1718, 1714, 1626.

REFERENCE EXAMPLE 21 5-Ethoxycarbonylimidazo 1,2-a!pyridin-3-ylmethyltrimethylammonium iodide

To a solution of 6.15 g (24.9 mmol) of 3-dimethylaminomethyl-5-ethoxycarbonylimidazo 1,2-a!pyridine was added a solutionof 3.71 g (26.1 mmol) of methyl iodide in 5 ml of acetonitrile. Themixture was stirred for 66 hours at room temperature. The solvent wasdistilled off, to give 10.50 g of the desired compound (quantitative, ayellow solid). This product was used in the subsequent reaction withoutfurther purification.

NMR(200 MHz,DMSO-d₆)δ: 1.42(3H,t,J=7.2 Hz), 2.94(9H,s), 4.57(2H,q,J=7.2Hz), 5.13(2H,s), 7.55(1H,dd,J=9.0, 7.2 Hz), 7.82(1H,dd,J=7.2, 1.4 Hz),8.06(1H,dd,J=9.0, 1.4 Hz), 8.09(1H,s).

REFERENCE EXAMPLE 22 5-Ethoxycarbonyl-3-nitroimidazo 1,2-a!pyridine

To a solution of 19.02 g (0.10 mol) of 5-ethoxycarbonylimidazo1,2-a!pyridine in 50 ml of conc. sulfuric acid was added dropwise, whilestirring under ice-cooling, 40 ml of conc. nitric acid. The mixture wasstirred for 20 minutes at the same temperature. The reaction mixture waspoured into ice-water, which was neutralized with a 10% aqueous solutionof NaOH. The resulting precipitates were collected by filtration, washedwith water and dried to afford 20.38 g of the desired compound (86.6%, apale yellow solid).

NMR(200 MHz,CDCl₃)δ: 1.41(3H,t,J=7.2 Hz), 4.48(2H,q,J=7.2 Hz),7.62-7.74(2H,m), 7.98(1H,m), 8.55(1H,s).

REFERENCE EXAMPLE 23 3-Amino-5-ethoxycarbonylimidazo 1,2-a!pyridine

To a solution of 2.35 g of 5-ethoxycarbonyl-3-nitroimidazo1,2-a!pyridine in 100 ml of ethanol was added 10% Pd-C (wet, 470 mg).The mixture was stirred for 110 hours at room temperature under hydrogenatmosphere. The catalyst was filtered off and washed with ethanol. Thefiltrate and the washing were combined, and the solvent was distilledoff. The residue was purified by column chromatography (eluent: ethylacetate) to afford 891 mg of the desired compound (43.4%, a dark reddishoil).

NMR(200 MHz,CDCl₃)δ: 1.46(3H,t,J=7.2 Hz), 4.22(2H,br), 4.48(2H,q,J=7.2Hz), 7.04(1H,dd,J=8.8, 7.2 Hz), 7.24(1H,s), 7.54(1H,dd,J=7.2, 1.2 Hz),7.74(1H,dd,J=8.8, 1.2 Hz).

REFERENCE EXAMPLE 24 3,4-Dihydro-1,3,7b-triazacyclopent cd!inden-4-one

To a suspension of 343 mg (8.58 mmol) of 60% sodium hydride (dispersionin oil) in 3 ml of DMF was added, while stirring at room temperature, asolution of 880 mg (4.29 mmol) of 3-amino-5-ethoxycarbonylimidazo1,2-a!pyridine in 5 ml of DMF. The mixture was stirred for 30 minutes at100° C. After cooling, the reaction mixture was poured into ice-water,washed with ethyl acetate. The aqueous layer was neutralized by theaddition of 6N-HCl. The resulting precipitates were collected byfiltration, washed with water, and dried to afford 100 mg of the desiredcompound (14.7%, a brown solid). The filtrate was extracted withchloroform, dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the residue was purified by column chromatography(eluent:ethyl acetate/ethanol=10:1) to afford 27 mg of the desiredcompound (4.0%, a yellow solid)

NMR(200 MHz,CDCl₃)δ: 7.67(1H,s), 7.75(1H,dd,J=8.6, 7.0 Hz),7.99(1H,d,J=7.0 Hz), 8.08(1H,d,J=8.6 Hz), 9.92(1H,br).

REFERENCE EXAMPLE 25 3,4-Dihydro-3-5-(phthalimido)pentan-1-yl!-1,3,7b-triazacyclopent cd!inden-4-one

To a suspension of 81 mg (0.51 mmol) of3,4-dihydro-1,3,7b-triazacyclopent cd!inden-4-one in 1 ml of DMF wasadded, while stirring under ice-cooling, 25 mg (0.63 mmol) of 60% sodiumhydride (dispersion in oil). The mixture was stirred for 15 minutes atthe same temperature. To the reaction mixture was added a solution of151 mg (0.51 mmol) of N-(5-bromopentyl)phthalimide in 1 ml of DMF. Themixture was stirred for two hours at 110° C. After cooling, the reactionmixture was poured into water, extracted with ethyl acetate. The extractwas washed with an aqueous saline solution and dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified by column chromatography (eluent: ethyl acetate/ethanol=10:1)to afford 40 mg of the desired compound (20.9%, a colorless solid).

NMR(200 MHz,CDCl₃)δ: 1.30-1.85(6H,m), 2.95(1H,m), 3.71(2H,t,J=7.0 Hz),4.44(1H,m), 6.88(1H,d,J=7.0 Hz), 7.16(1H,dd,J=9.2, 7.0 Hz), 7.16(1H,s),7.38(1H,d,J=9.2 Hz), 7.67-7.90(4H,m).

REFERENCE EXAMPLE 26 5-Ethoxycarbonyl-2-methyl-3-nitroimidazo1,2-a!pyridine

To a solution of 1.02 g (5.0 mmol) of 5-ethoxycarbonyl-2-methyl-imidazo1,2-a!pyridine in 2.5 ml of conc. sulfuric acid was added dropwise,while stirring under ice-cooling, 2.0 ml of conc. nitric acid. Themixture was stirred for 10 minutes at the same temperature. The reactionmixture was poured into ice-water, whose pH was adjusted to 3-with a 10%aqueous solution of NaOH. The resulting crystalline precipitates werecollected by filtration, washed with water and dried, followed byfurther purification by column chromatography (eluent: ethyl acetate) toafford 752 mg of the desired compound (60.4%, a yellow solid).

NMR(200 MHz,CDCl₃)δ: 1.41(3H,t,J=7.2 Hz), 2.81(3H,s), 4.46(2H,q,J=7.2Hz), 7.58-7.68(2H,m), 7.84(1H,m).

REFERENCE EXAMPLE 27 3-Amino-5-ethoxycarbonyl-2-methyl-imidazo1,2-a!pyridine

To a solution of 300 mg of 5-ethoxycarbonyl-2-methyl-3-nitroimidazo1,2-a!pyridine in 20 ml of methanol was added 10%Pd-C (wet, 90 mg). Themixture was stirred for two hours at room temperature under hydrogenatmosphere. The catalyst was filtered off and washed with methanol. Thefiltrate and the washing were combined, and the solvent was filteredoff. The residue was purified by column chromatography (eluent: ethylacetate) to afford 184 mg of the object product (69.7%, an orange solid)

NMR(200 MHz,CDCl₃)δ: 1.46(3H,t,J=7.2 Hz), 2.45(3H,s), 4.02(2H,br),4.48(2H,q,J=7.2 Hz), 6.99(1H,dd,J=8.8, 7.2 Hz), 7.52(1H,dd,J=7.2, 1.2Hz), 7.66(1H,dd,J=8.8, 1.2 Hz).

REFERENCE EXAMPLE 28

3,4-Dihydro-2-methyl-1,3,7b-triazacyclopent cd!inden-4-one

To a suspension of 610 mg (15.3 mmol) of 60% sodium hydride (dispersionin oil) in 5 ml of DMF was added, while stirring at room temperature, asolution of 1.67 g (7.62 mmol) of3-amino-5-ethoxycarbonyl-2-methyl-imidazo 1,2-a!pyridine in 5 ml of DMF.The mixture was stirred for 10 minutes, then for 30 minutes at 100° C.After cooling, the reaction mixture was poured into ice-water, andwashed with chloroform. To the aqueous layer was added 6N-HCl to adjustthe pH to 5-6. The resulting precipitates were collected by filtration,washed with water and diethyl ether, successively, and dried to afford357 mg of the desired compound (27.0%, a brown solid).

NMR(200 MHz,CDCl₃)δ: 2.02(3H,s), 7.02-7.40(3H,m), 10.45(1H,br).

REFERENCE EXAMPLE 29 3,4-Dihydro-3-5-(phthalimido)pentan-1-yl!-2-methyl-1,3,7b-triazacyclopentcd!inden-4-one

To a suspension of 277 mg (1.60 mmol) of3,4-dihydro-2-methyl-1,3,7b-triazacyclopent cd!inden-4-one in 3 ml ofDMF was added, while stirring under ice-cooling, 77 mg (1.93 mmol) of60% sodium hydride (dispersion in oil). The mixture was stirred for 15minutes at the same temperature. To the reaction mixture was added 521mg (1.76 mmol) of N-(5-bromopentyl)phthalimide. The mixture was stirredfor one hour at 110° C. After cooling, the reaction mixture was pouredinto water, and extracted with ethyl acetate. The extract solution waswashed with an aqueous saline solution, and dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified by column chromatography (eluent: ethyl acetate/ethanol=10:1)to afford 410 mg of the desired compound (66.0%, a pale brown solid).

NMR(200 MHz,CDCl₃)δ: 1.25-1.80(6H,m), 2.06(3H,s), 2.99(1H,m),3.67(2H,t,J=7.0 Hz), 4.31(1H,m), 6.94(1H,dd,J=6.8, 1.2 Hz),7.13(1H,dd,J=9.0, 6.8 Hz), 7.29(1H,dd,J=9.0, 1.2 Hz), 7.66-7.90(4H,m).

REFERENCE EXAMPLE 304,5-Dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione

To a solution of 2.64 g (7.55 mmol) of5-ethoxycarbonyl-3-trichloroacetylimidazo 1,2-a!pyridine in 20 ml ofacetonitrile was added 2.5 ml of 25% aqueous ammonia. The mixture wasstirred for 5 hours at room temperature. The resulting crystals werecollected by filtration and washed with acetonitrile to give 393 mg ofthe desired compound (27.8%, pale brown solid).

NMR(200 MHz,DMSO-d₆)δ: 7.84(1H,dd,J=8.8, 7.4 Hz), 8.01(1H,dd,J=7.4, 1.0Hz), 8.22(1H,dd,J=8.8, 1.0 Hz), 8.53(1H,s).

REFERENCE EXAMPLE 31 5- 2-4-(Amino)phenyl!ethan-1-ylamino!-3-ethoxycarbonyl-2-methylimidazo1,2-a!pyridine

A mixture of 4.07 g (17.1 mmol) of5-chloro-3-ethoxycarbonyl-2-methylimidazo 1,2-a)pyridine, 3.48 g (25.6mmol) of 2-(4-aminophenyl)ethylamine and 4.41 g (34.1 mmol) ofN,N-diisopropylethylamine in 60 ml of acetonitrile was heated for 64hours under reflux with stirring. After cooling, the solvent wasdistilled off. To the residue was added chloroform. The residue waswashed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled off. The residue was purified by columnchromatography (eluent: chloroform/methanol=30:1) and recrystallizedfrom ethyl acetate-n-hexane to give 4.37 g of the desired compound(75.7%, pale brown crystals).

NMR(200 MHz,CDCl₃)δ: 1.44(3H,t,J=7.2 Hz), 2.66(3H,s), 2.95(2H,m),3.42(2H,m), 3.62(2H,br), 4.39(2H,q,J=7.2 Hz), 5.95(1H,dd,J=8.0, 1.2 Hz),6.65(2H,m), 6.91(1H,dd,J=8.4, 1.2 Hz), 7.15(2H,m), 7.33(1H,dd,J=8.4, 8.0Hz), 8.75(1H,br).

REFERENCE EXAMPLE 32 1- 2-4-(Amino)phenyl!ethan-1-yl)-1,2-dihydro-3-methyl-1,4,7b-triazacyclopentcd!inden-2-one

To a suspension of 80 mg (2.0 mmol) of 60% sodium hydride (dispension inoil) in 10 ml of DMF was added, while stirring at room temperature, 338mg (1.0 mmol) of 5- 2-4-(amino)phenyl!ethan-1-ylamino!-3-ethoxycarbonyl-2-methylimidazo1,2-a!pyridine. The mixture was stirred for 30 minutes. The reactionmixture was poured into water, extracted with ethyl acetate. The extractwas washed with an aqueous saline solution, dried over anhydrousmagnesium sulfate. The solvent was distilled off. The residue waspurified by column chromatography (eluent: ethyl acetate) to give 151 mgof the desired compound (51.7%, pale brown solid).

NMR(200 MHz,CDCl₃)δ: 2.82(3H,s), 3.01(2H,t,J=7.0 Hz), 3.61(2H,br),4.21(2H,t,J=7.0 Hz), 6.39(1H,d,J=7.4 Hz), 6.55(2H,m), 6.93(2H,m),7.41(1H,d,J=8.6 Hz), 7.58(1H,dd,J=8.6, 7.4 Hz).

REFERENCE EXAMPLE 33 5-Chloro-3-trichloroacetylimidazo 1,2-a!pyridine

To a solution of 45.77 g (0.30 mol) of 5-chloroimidazo 1,2-a!pyridineand 120.9 g (0.99 mol) of 4-dimethylaminopyridine in 500 ml ofchloroform was added dropwise 163.5 g (0.90 mol) of trichloroacetylchloride. The mixture was heated for 43 hours under reflux. Aftercooling, the reaction mixture was washed with an aqueous solution ofsodium hydrogencarbonate, dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified by columnchromatography (eluent: ethyl acetate/n-hexan=1:1) to give 7.41 g of thedesired compound (8.3%, pale brown solid).

NMR(200 MHz,CDCl₃)δ: 7.24(1H,dd,J=7.4, 1.2 Hz), 7.58(1H,dd,J=8.8, 7.4Hz), 7.82(1H,dd,J=8.8, 1.2 Hz), 8.79(1H,s).

REFERENCE EXAMPLE 34 N- 5-Imidazo1,2-a!pyridylmethyl!hexamethylenetetraminium.chloride

To a suspension of 5.78 g (28.46 mmol) of 5-chloromethylimidazo1,2-a!pyridine-hydrochloride and 4.79 g (34.16 mmol) ofhexamethylenetetramin in 100 ml of acetonitrile was heated for 30minutes under reflux. The reaction mixture was cooled to roomtemperature.

The resulting precipitates were collected by filtration, washed with 20ml of acetonitrile and 20 ml of ether, and dried under reduced pressureto give 8.61 g of the desired compound (98.6%, white solid).

NMR(200 MHz,DMSO-d₆)δ: 4.41-4.78(12H,m), 5.40(2H,s), 7.30(1H,d,J=7.0Hz), 7.48(1H,dd,J=8.6, 7.0 Hz), 7.83-7.89(2H,m), 8.68(1H,s). IR(KBr):2831, 1460, 1375 cm⁻¹

REFERENCE EXAMPLE 35 5-(tert-Butoxycarbonylamino)methylimidazo1,2-a!pyridine

To a solution of 20 ml of purified water, 100 ml of ethanol and 24 ml of12N HCl was added 8.61 g (28.06 mmol) of N-(5-imidazo1,2-a!pyridylmethyl)hexamethylenetetraminium-chloride. The reactionmixture was stirred for 12 hours at 50° C. The reaction mixture wasconcentrated to 30 ml of volume under reduced pressure. The resultingprecipitates anmmonium chloride were collected by filtration. Thefiltrate was completely concentrated under reduced pressure. To theresidue was added 50 ml of purified water and 50 ml of THF, to give thehomogeneous solution. To the solution was added 12 ml (84.18 mmol) oftriethylamine and 7.35 g (33.67 mmol) of di-tert-butyl dicarbonate. Themixture was stirred for one hour at room temperature. To the reactionmixture was added 100 ml of purified water and 100 ml of ethyl acetate,and the mixture was extracted. The organic layer was washed with 100 mlof a saturated saline, dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give4.20 g of the desired compound (60.5%, white solid).

NMR(200 MHz,CDCl₃) δ: 1.47 (9H, s), 4.61(2H,d,J=6.0 Hz), 5.13(1H,brs),6.76(1H,d,J=6.6 Hz), 7.18(1H,dd,J=8.8, 6.6 Hz), 7.61(1H,d,J=8.8 Hz),7.69(2H,s). IR(KBr): 1707, 1450, 1269, 1167 cm⁻¹

REFERENCE EXAMPLE 364,5-Dihydro-4-(tert-butoxycarbonyl)-3H-1,4,8b-triazaacenaphthylen-3-one

To a solution of 989 mg (4.0 mmol) of5-(tert-butoxycarbonylamino)methylimidazo 1,2-a!pyridine and 2200 mg(18.0 mmol) of 4-(N,N-dimethylamino)pyridine in 25 ml of chloroform wasadded dropwise 1.34 ml (12.0 mmol) of trichloroacetyl chloride at roomtemperature. The reaction mixture was heated for 5 hours under reflux.The reaction mixture was poured into ice-water. The mixture wasneutralized with a saturated aqueous solution of sodiumhydrogencarbonate. To the mixture was added 100 ml of chloroform forextraction of the desired compound. The organic layer was washed with100 ml of a saturated saline, and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:chloroform:methanol=20:1) to give 492 mg of the desired compound (45.0%,pale yellow solid).

NMR(200 MHz,CDCl₃)δ: 1.58(9H,s), 5.28(2H,s), 6.92(1H,d,J=7.0 Hz),7.45(1H,dd,J=9.2, 7.0 Hz), 7.65(1H,d,J=9.2 Hz), 8.39(1H,s). IR(KBr):1714, 1515, 1309, 1149 cm⁻¹

REFERENCE EXAMPLE 374,5-Dihydro-3H-1,4,8b-triazaacenaphthylene-3-one-hydrochloride

To a solution of 95.7 mg (0.35 mmol) of4,5-dihydro-4-(tert-butoxycarbonyl)-3H-1,4,8b-triazaacenaphthylen-3-onein 100 ml of ethanol was added 0.09 ml (1.05 mmol) of 12N HCl. Themixture was stirred for one hour at room temperature. The resultingcrystalline precipitates were collected by filtration, washed with asmall volume of ethanol and ether and dried to give 56.1 mg of thedesired compound (76.4%, white solid).

NMR(200 MHz,DMSO-d₆)δ: 5.12(2H,s), 7.44(1H,d,J=7.4 Hz), 7.85(1H,d,J=9.2Hz), 7.99(1H,dd,J=9.2, 7.4 Hz), 8.50(1H,brs), 8.62(1H,s). IR(KBr): 1677,1479, 1360 cm⁻¹

REFERENCE EXAMPLE 38 1,2-Dihydro-1,4,7b-triazacyclopentcd!inden-2-one.2NaCl

i) Synthesis of 5-amino-3-carbethoxyimidazo 1,2-a!-pyridine

In 1250 ml of ether was suspended 56.0 g (500 mM) of potassiumtert-butoxide and while the suspension was stirred vigorously, asolution of 37.0 g (500 mM) of ethyl formate and 61.3 g (500 mM) ofethyl chloroacetate in 100 ml of ether was added dropwise at roomtemperature over 15 minutes. The reaction mixture was stirred at roomtemperature for 30 minutes and the precipitate that formed was recoveredby filtration. The precipitate was rinsed with 50 ml of ether and driedin vacuo to give 93.13 g of ethyl 2-chloro-2-formylacetate potassiumsalt as light-yellow solid. In 40 ml of ethanol was suspended 7.59 g(40.0 mM) of this ethyl 2-chloro-2-formylacetate potassium salt as wellas 2.18 g (20.0 mM) of 2,6-diaminopyridine and following addition of 2.3ml (40 mM) of acetic acid, the mixture was refluxed for 3 hours. Aftercompletion of the reaction, the precipitate that formed was recovered byfiltration and rinsed with 10 ml of ethanol. The filtrate and the washeswere pooled and neutralized with aqueous NaCO₃ solution, and the solventwas distilled off under reduced pressure. The residue was extracted with100 ml of ethyl acetate and the organic layer was washed with 100 ml ofsaturated aqueous NaCl solution and dried over MgSO₄. The solvent wasdistilled off under reduced pressure and the residue was washed withether to provide 1.65 g of the title compound as light-yellow solid. Thewashes were concentrated and the residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate) to provide 0.61 g of thetitle compound (total yield 2.26 g, percent yield 55.1%).

¹ H-NMR(200 MHz,CDCl₃)δ: 1.42(3H,t,J=7.2 Hz), 4.37(2H,q, J=7.2 Hz),6.10(1H,dd,J=7.2, 1.0 Hz), 6.84(2H,br s,NH₂), 7.07(1H,dd,J=8.6, 1.2 Hz),7.32(1H,t,J=8.6 Hz), 8.39(1H,s). IR(KBr): 3225, 1689, 1647 cm⁻¹.

ii) Synthesis of 1,2-dihydro-1,4,7b-triazacyclopent cd!inden-2-one.2NaCl

To a solution prepared by dissolving 1.44 g (7.0 mM) of3-carbethoxy-5-aminoimidazo 1,2-a!pyridine in 10 ml of acetonitrilefollowed by addition of 3.2 ml (14.0 mM) of 25% sodiummethoxide-methanol and the mixture was refluxed for 1 hour. Aftercompletion of the reaction, 1.15 ml (14.0 mM) of 12N-hydrochloric acidwas added to the reaction mixture under ice-cooling and the solvent wasthoroughly distilled off under reduced pressure to provide 2.01 g (yield100%) of a crude product as tan-colored solid.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 7.05 (1H,d,J=7.4 Hz), 7.66 (1H,d,J=8.6 Hz),7.85(1H,dd,J=8.6, 7.4 Hz), 8.41(1H,s). IR(KBr): 3452, 1699, 1668 cm⁻¹.

REFERENCE EXAMPLE 39 1,2-Dihydro-1,4,7b-triazacyclopent cd!inden-2-onesodium salt

To a solution prepared by dissolving 51.3 g (25.0 mM) of5-amino-3-carbethoxyimidazo 1,2-a!pyridine in 500 ml of ethanol wasadded 114 ml (50.0 mM) of 25% sodium methoxide-methanol and the mixturewas refluxed for 3 hours. After completion of the reaction, theprecipitate that formed was recovered by filtration, rinsed with 50 mlof ethanol, and dried in vacuo to provide 32.66 g (yield 72.1%) of thetitle compound as gray powders.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 6.47(1H,d,J=7.4 Hz), 7.02(1H,d, J=8.4 Hz),7.45(1H,dd,J=8.4, 7.4 Hz), 7.78(1H,s).

REFERENCE EXAMPLE 40 3-Carbethoxy-5-chloromethylimidazo 1,2-a!pyridinesulfate

i) Synthesis of 3-carbethoxy-5-methylimidazo 1,2-a!-pyridine

In 10 ml of ether was suspended 560 mg (5.0 mM) of potassiumtert-butoxide and while the suspension was vigorously stirred, asolution of ethyl formate:370 mg (5.00 mM) and ethyl chloroformate: 613mg (5.00 mM) in 10 ml of ether was added dropwise over 3 minutes at roomtemperature. This mixture was stirred at room temperature for 30 minutesand the precipitate that formed was recovered by filtration and rinsedwith a small amount of ether. This precipitate was dried in vacuo togive 700 mg (yield 73.8%) of ethyl 2-chloro-2-formylacetate potassiumsalt as light-yellow solid. Then, 700 mg (3.69 mM) of ethyl2-chloro-2-formylacetate potassium salt and 399 mg (3.69 mM) of6-amino-2-methylpyridine were mixed with 20 ml of ethanol and afteraddition of 0.53 ml (9.23 mM) of acetic acid, the whole mixture wasrefluxed for 3 hours. After completion of the reaction, the solvent wasdistilled off under reduced pressure and the residue was diluted with 20ml of ethyl acetate and 20 ml of purified water. Then, saturated aqueousNaHCO₃ solution was added until the water layer became pH 8. Thismixture was extracted with 40 ml of ethyl acetate and the organic layerwas washed with 30 ml of saturated aqueous NaCl solution and dried overMgSO₄. The solvent was then distilled off under reduced pressure and theresidue was purified by silica gel column chromatography (eluent: ethylacetate) to provide 430 mg (yield 57.1%) of the title compound aslight-yellow liquid.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.42(3H,t,J=7.0 Hz), 2.82(3H,s),4.38(2H,q,J=7.0 Hz), 6.81(1H,d,J=7.0 Hz), 7.36(1H,dd, J=8.8, 7.0 Hz),7.62(1H,d,J=8.8 Hz), 8.30(1H,s).

ii) Synthesis of 3-carboethoxy-5-chloromethylimidazo 1,2-a!pyridine

To a solution prepared by dissolving 430 mg (2.06 mM) of3-carbethoxy-5-methylimidazo 1,2-a!pyridine in 10 ml of ethyl acetatewas added 330 mg (2.67 mM) of N-chlorosuccinimide. Then, 1.03 ml (1.03mM) of 1N-tri-fluoroacetic acid-ethyl acetate was added dropwise at roomtemperature. The mixture was stirred under argon gas at room temperaturefor 14 hours. After the reaction, the reaction mixture was poured in 30ml of saturated aqueous NaHCO₃ solution with ice-cooling and the mixturewas extracted with 20 ml of ethyl acetate. The organic layer was washedwith 30 ml of saturated aqueous NaCl solution and dried over MgSO₄. Thesolvent was then distilled off under reduced pressure and the residuewas purified by silica gel column chromatography (eluent: ethyl acetate)to provide 350 mg (yield 71.2%) of the title compound as yellow liquid.

¹ H-NMR(200 MHz,CDCl₃)δ: 1.45(3H,t,J=7.2 Hz), 4.44(2H,q,J=7.2 Hz),5.44(2H,s), 7.08(1H,d,J=7.0 Hz), 7.42(1H,dd,J=8.8, 7.0 Hz),7.80(1H,d,J=8.8 Hz), 8.35(1H,s).

iii) Synthesis of 3-carbethoxy-5-chloromethylimidazo 1,2-a!pyridinesulfate

To a solution prepared by dissolving 43.91 g (215.03 mM) of3-carbethoxy-5-methylimidazo 1,2-a!pyridine in 200 ml of ethyl acetatewas added 31.58 g (236.53 mM) of N-chlorosuccinimide. Then, 1.66 ml(21.50 mM) of trifluoroacetic acid was added dropwise at roomtemperature. This mixture was stirred under argon gas at roomtemperature for 14 hours. After completion of the reaction, the reactionmixture was poured in 300 ml of saturated aqueous NaHCO₃ solution withice-cooling and extracted with 200 ml of ethyl acetate. The organiclayer was washed with 300 ml of saturated aqueous NaCl solution anddried over MgSO₄ and the solvent was distilled off under reducedpressure to recover 22.15 g of crude 3-carbethoxy-5-chloromethylimidazo1,2-a!pyridine as tan-colored liquid. To a solution prepared bydissolving 22.15 g of this crude 3-carbethoxy-5-chloromethylimidazo1,2-a!pyridine in 200 ml of acetonitrile was added 4.95 ml (92.80 mM) ofsulfuric acid with ice-cooling and the mixture was stirred. The purifiedprecipitate was recovered by filtration, rinsed with a small amount ofacetonitrile, and dried in vacuo to provide 16.20 g (yield 22.4%) of thetitle compound as orchre powders.

¹ H-NMR(200 MHz,DMSO-d₆)δ: 1.38(3H,t,J=7.0 Hz), 4.41(2H,q, J=7.0 Hz),5.60(2H,s), 7.62(1H,d,J=7.0 Hz), 7.83(1H,dd,J=7.6, 7.0 Hz),8.00(1H,d,7.6 Hz), 8.61(1H,s).

Preparation Example 1 (as one coated tablet)

    ______________________________________    (1)      Compound of Example 1                                10.0 mg    (2)      Lactose            60.0 mg    (3)      Corn starch        35.0 mg    (4)      Gelatin             3.0 mg    (5)      Magnesium stearate  2.0 mg    ______________________________________

A mixture of 10.0 mg of the compound of Example 1, 60.0 mg of lactoseand 35.0 mg of corn starch was granulated through a 1 mm mesh screen,using 0.03 ml of an aqueous solution of 10 weight % gelatin (3.0 mg interms of gelatin), which was dried at 40° C. and screened again. Thegranules thus obtained were mixed with 2.0 mg of magnesium stearate andcompressed. The core tablet thus obtained was coated with a suspensionof sucrose, titanium dioxide and talc in gum arabic, which was polishedwith bees wax.

Preparation Example 2 (as one tablet)

    ______________________________________    (1)      Compound of Example 1                                10.0 mg    (2)      Lactose            70.0 mg    (3)      Corn starch        50.0 mg    (4)      Soluble starch      7.0 mg    (5)      Magnesium stearate  3.0 mg    ______________________________________

A mixture of 10.0 mg of the compound of Example 1 and 3.0 mg ofmagnesium stearate was granulated with 0.07 ml of an aqueous solution ofsoluble starch (7.0 mg in terms of soluble starch), which was dried and,then mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Themixture was compressed to obtain a tablet.

Preparation Example 3

    ______________________________________    (1)   Compound of Example 1     5.0 mg    (2)   Common salt              20.0 mg    (3)   Distilled water to make the whole volume                                     2 ml    ______________________________________

In distilled water were dissolved 5.0 mg of the compound of Example 1and 20.0 mg of common salt. To the solution was added distilled water tomake the whole volume 2.0 ml. The solution was subjected to filtration,which was filled into a 20 ml-ampoule under sterile conditions. Theampoule was sterilized and sealed to provide an injectable solution.

Industrial applicability

The present invention relates to a novel tricyclic compound, which isuseful as a medicine having an excellent activity of inhibitingplatelet-derived growth factor (PDGF), antihypertensive activity,ameliorating activity of renal failure and lowering the cholesterollevel, a process for producing the compound, and a pharmaceuticalcomposition containing the compound.

We claim:
 1. A compound of the formula: ##STR119## wherein ring A is a5-membered nitrogen-containing heterocyclic ring, having two nitrogenatoms as the hetero-atoms, which is optionally substituted with oxo orthioxo;ring Q is optionally substituted with one to three substituentsselected from (i) halogen atom, (ii) alkyl group, (iii) halogeno-alkylgroup, (iv) alkoxyl group, (v) halogeno-alkoxyl group, (vi) alkylthiogroup, (vii) halogeno-alkylthio group, (viii) hydroxyl group, (ix)carboxyl group, (x) cyano group, (xi) nitro group, (xii) amino group,(xiii) mono-alkyl amino group, (xiv) di-alkyl amino group, (xv) formylgroup, (xvi) mercapto group, (xvii) alkyl-carbonyl group, (xviii)alkoxyl-carbonyl group, (xix) sulfonyl group, (xx) alkylsulfonyl group,(xxi) carbamoyl group, (xxii) mono-alkyl-carbamoyl group, or (xxiii)di-alkyl-carbamoyl group; with the proviso that when Q is substituted bymore than one substituent selected from (ix) carboxyl group, (x) cyanogroup, (xi) nitro group, (xv) formyl group, (xvii) alkyl-carbonyl group,(xviii) alkoxyl-carbonyl group, (xix) sulfonyl group or (xx)alkylsulfonyl group, these substituents are substituted in the metaposition to each other and there is a maximum of two of thesesubstituents present on ring Q; Y is a group of the formula: ##STR120##wherein B is an optionally substituted divalent C₁₋₆ hydrocarbonselected from the group consisting of a C₁₋₅ alkylene group, C₂₋₁₆alkenylene group, C₂₋₁₆ alkynylene group, phenylene group and acombination thereof; X is a bond, an oxygen atom or a sulfur atom; R² isa hydrogen atom or an optionally substituted C₁₋₁₈ hydrocarbon groupselected from an alkyl group, a cycloalkyl group, an alkenyl group, anaralkyl group, or an aryl group, or R² and B may form a ring togetherwith the adjacent nitrogen atom; and R^(3a) is an election-withdrawinggroup; or R² and R^(3a) may form a ring together with the adjacentnitrogen atom; and R¹ is a hydrogen atom, a halogen atom, an optionallysubstituted C₁₋₁₈ hydrocarbon group selected from an alkyl group, acycloalkyl group, an alkenyl group, an aralkyl group, or an aryl group,or an C₁₋₆ acyl group; wherein when the hydrocarbon group of R¹ or R² issubstituted, then the hydrocarbon group is substituted as follows:thealkyl, cycloalkyl, alkenyl and alkynyl groups are substituted with oneto five substituents selected from the group consisting of (i) nitrogroup, (ii) hydroxyl group, (iii) cyano group, (iv) carbamoyl group, (v)mono-alkyl-carbamoyl group, (vi) di-alkyl-carbamoyl group, (vii)carboxyl group, (viii) alkoxyl-carbonyl group, (ix) sulfonyl group, (x)halogen atom, (xi) alkoxyl group, (xii) phenoxy group, (xiii)halogenophenoxy group, (xiv) alkylthio group, (xv) mercapto group, (xvi)phenylthio group, (xvii) pyridylthio group, (xviii) alkylsulfinyl group,(xix) alkylsulfonyl group, (xx) amino group, (xxi) acylamino group,(xxii) mono-alkylamino group, (xxiii) di-alkylamino group, (xxiv) 4 to 6member cyclic amino group, (xxv) acyl group, (xxvi) benzoyl group and(xxvii) 5 to 10 member heterocyclic group; the aralkyl group issubstituted with one to four substituents selected from the groupconsisting of (i) halogen atom, (ii) alkyl group, (iii) halogeno-alkylgroup, (iv) alkenyl group, (v) acyl group (vi) alkoxyl group, (vii)nitro group (viii) cyano group, (ix) hydroxyl group, (x)alkoxyl-carbonyl group, (xi) carbamoyl group, (xii) mono-alkyl-carbamoylgroup, (xiii) di-alkyl-carbamoyl (xiv) mono- alkenyl-carbamoyl group,and (xv) di-alkenyl-carbamoyl group; and the aryl group is substitutedwith one to four substituents selected from the group consisting of (i)halogen atom, (ii) alkyl group, (iii) halogeno-alkyl group, (iv) alkenylgroup, (v) acyl group, (vi) alkoxyl group, (vii) nitro group, (viii)cyano group, (ix) hydroxyl group, (x) alkoxyl-carbonyl group, (xi)carbamoyl group, (xii) mono-alkyl-carbamoyl group, (xiii)di-alkyl-carbamoyl (xiv) mono-alkenyl-carbamoyl group, (xv)di-alkenyl-carbamoyl group and (xvi) oxo group; and wherein when thedivalent C₁₋₆ hydrocarbon of B is substituted, the divalent C₁₋₁₆hydrocarbon is substituted as follows:the alkvlene, alkenvlene andalkynylene groups are substituted with an optionally substituted alkylgroup, optionally substituted aralkyl group, or optionally substitutedaryl group, and the phenylene group is substituted with one to foursubstituents selected from (i) halogen atom, (ii) alkyl group, (iii)alkoxyl group, (iv) alkylthio group, (v) hydroxyl group, (vi) carboxylgroup. (vii) cyano group, (viii) nitro group, (ix) amino group, (x)mono-alkyl amino group, (xi) di-alkyl amino group, (xii) formyl group,(xiii) mercapto group, (xiv) alkyl-carbonyl group, (xv) alkoxyl-carbonylgroup, (xvi) sulfonyl group, (xvii) alkylsulfonyl group, (xviii)carbamoyl group, (xix) mono-alkyl-carbamoyl group, or (xx)di-alkyl-carbamoyl group: with the proviso that when the phenylene groupis substituted by more than one substituent selected from (vi) carboxylgroup, (vii) cyano group. (viii) nitro group, (xii) formyl group, (xiv)alkyl-carbonyl group, (xv) alkoxyl-carbonyl group, (xvi) sulfonyl groupor (xvii) alkylsulfonyl group, these substituents are substituted in themeta position to each other and there is a maximum of two of thesesubstituents present on the phenylene group: or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1, wherein the ring Q isoptionally substituted with one to three substituents selected from thegroup consisting of (i) halogen atom, (ii) a C₁₋₄ alkyl group, (iii) aC₁₋₄ alkoxy group, (iv) a C₁₋₄ alkylthio group, (v) a hydroxyl group(vi) a carboxyl group, (vii) a cyano group, (viii) a nitro group, (ix)an amino group, (x) a mono- or di- C₁₋₄ alkyl group, (xi) a formalgroup, (xii) a mercapto group, (xiii) a C₁₋₄ alkyl-carbonyl group, (xiv)a C₁₋₄ alkoxy-carbonyl group, (xv) a sulfonyl group, (xvi) a C₁₋₄ alkylsulfonyl group, (xvii) a carbamoyl group and (xviii) a mono- or di- C₁₋₄alkyl-carbamoyl group; with the proviso that when Q is substituted bymore than one substituent selected from (vi) a carboxyl group, (vii) acyano group, (viii) a nitro group, (xi) a formyl group, (xiii) a C₁₋₄alkyl-carbonyl group, (xiv) a C₁₋₄ alkoxyl-carbonyl group, (xv) a sulfogroup, or (xvi) a C₁₋₄ alkyl sulfonyl group, these substituents aresubstituted in the meta position to each other and there is a maximum oftwo of these substituents present on ring Q.
 3. A compound of claim 1,wherein the ring Q is unsubstituted.
 4. A compound of claim 1, whereinR¹ is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted aralkylgroup, an optionally substituted aryl group, or an acyl group selectedfrom an alkoxy carbonyl group, an alkyl carbamoyl group or an alkanoylgroup.
 5. A compound of claim 4, wherein R¹ is a hydrogen atom, a C₁₋₆alkyl group or a phenyl group.
 6. A compound of claim 1, wherein R² is ahydrogen atom, an optionally substituted alkyl group or an optionallysubstituted alkenyl group.
 7. A compound of claim 1, wherein theelectron-withdrawing group is (i) --SO₂ R⁴ wherein R⁴ is an optionallysubstituted hydrocarbon group, (ii) --CO--R⁵ wherein R⁵ is a hydrogenatom or an optionally substituted hydrocarbon group, (iii) --COOR⁶wherein R⁶ is an optionally substituted hydrocarbon group, (iv)--CON(R⁷)R⁸ wherein R⁷ and R⁸ respectively are a hydrogen atom or anoptionally substituted hydrocarbon group, or, R⁷ and R⁸ form a ringtogether with the adjacent nitrogen atom, (v) a nitro group or (vi) acyano group.
 8. A compound of claim 1, wherein B is a C₂₋₁₀ alkylenegroup.
 9. A compound of claim 1, wherein B is a group of the formula:##STR121## wherein p and q are independently an integer of 0 to
 5. 10. Acompound of claim 1, wherein B is a C₃₋₈ alkylene group.
 11. A compoundof claim 1, which is one of the formula: ##STR122## wherein X¹ is anoxygen atom or a sulfur atom, and the other symbols have the samemeaning as defined in claim 1, or a pharmaceutically acceptable saltthereof.
 12. A compound of claim 1, which is of the formula: ##STR123##wherein X¹ is an oxygen atom or a sulfur atom, and the other symbolshave the same meaning as defined in claim 1, or a pharmaceuticallyacceptable salt thereof.
 13. A compound of claim 11, wherein the ring Qis unsubstituted.
 14. A compound of claim 11, wherein R¹ is a hydrogenatom, an optionally substituted alkyl group or an optionally substitutedalkenyl group.
 15. A compound of claim 11, wherein R¹ is a hydrogen atomor a C₁₋₆ alkyl group.
 16. A compound of claim 11, wherein R² is ahydrogen atom or a C₁₋₆ alkyl group.
 17. A compound of claim 11, whereinR² is a hydrogen atom.
 18. A compound of claim 11, wherein X¹ is anoxygen atom.
 19. A compound of claim 11, wherein X¹ is a sulfur atom.20. A compound of claim 11, wherein B is a C₂₋₁₀ alkylene group.
 21. Acompound of claim 11, wherein B is a C₃₋₈ alkylene group.
 22. A compoundof claim 11, wherein the electron-withdrawing group represented by R³ is--SO₂ R^(4a) wherein R^(4a) is an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted aralkylgroup or an optionally substituted aryl group.
 23. A compound of claim22, wherein R^(4a) is a halogeno-C₁₋₆ alkyl group.
 24. A compound ofclaim 1 represented by the formula: ##STR124## wherein ring A^(a) is a 5membered nitrogen-containing heterocyclic ring which is optionallysubstituted with one oxo group, D is a bond or an optionally substituteddivalent C₁₋₁₆ hydrocarbon group selected from the group consisting of aC₁₋₁₅ alkylene group, C₂₋₁₆ alkenylene group, C₂₋₆ alkynylene group,phenylene group and a combination thereof; ring W is an optionallysubstituted nitrogen-containing heterocyclic ring, ring Q is optionallysubstituted as defined in claim 1, and R³ is an electron withdrawinggroup;wherein when the divalent C₁₋₁₆ hydrocarbon of D is substituted,the divalent C₁₋₁₆ hydrocarbon is substituted as follows:the alkylene,alkenylene and alkynylene groups are substituted with an optionallysubstituted alkyl, optionally substituted aralkyl or optionallysubstituted aryl as defined for R¹ in claim 1, the phenylene group issubstituted with one to four substituents selected from (i) halogenatom, (ii) alkyl group, (iii) alkoxyl group, (iv) alkylthio group, (v)hydroxyl group, (vi) carboxyl group, (vii) cyano group, (viii) nitrogroup, (ix) amino group, (x) mono-alkyl amino group, (xi) di-alkyl aminogroup, (xii) formyl group, (xiii) mercapto group, (xiv) alkyl-carbonylgroup, (xv) alkoxy-carbonyl group, (xvi) sulfonyl group, (xvii)alkylsulfonyl, (xviii) carbamoyl group, (xix) mono-alkyl-carbamoylgroup, or (xx) di-alkyl-carbamoyl group; with the proviso that when thephenylene group is substituted by more than one substituent selectedfrom (vi) carboxyl, (vii) cyano, (viii) nitro, (xii) formyl, (xiv)alkyl-carbonyl group, (xv) alkoxyl-carbonyl group. (xvi) sulfonyl groupor (xvii) alkylsulfonyl group, these substituents are substituted in themeta position to each other and there is a maximum of two of thesesubstituents present on the phenylene group; and wherein ring W isoptionally substituted with one to three substituents selected from (i)halogen atom, (ii) alkyl group, (iii) halogeno-alkyl group, (iv) alkoxylgroup, (v) halogeno-alkoxyl group, (vi) alkylthio group, (vii)halogeno-alkylthio group, (viii) hydroxyl group, (ix) carboxyl group,(x) cyano group, (xi) nitro group, (xii) amino group, (xiii) mono-alkylamino group, (xiv) di-alkyl amino group, (xv) formyl group, (xvi)mercapto group, (xvii) alkyl-carbonyl group, (xviii) alkoxyl-carbonylgroup, (xix) sulfonyl group, (xx) alkylsulfonyl group, (xxi) carbamoylgroup, (xxii) mono-alkyl-carbamoyl group, or (xxiii) di-alkyl-carbamoylgroup; or a pharmaceutically acceptable salt thereof.
 25. A compound ofclaim 24, wherein ##STR125## wherein ring Q is of the same meaning ofclaim
 24. 26. A compound of claim 24, wherein D is an optionallysubstituted divalent hydrocarbon.
 27. A compound of claim 24, whereinring W is an optionally substituted 5- or 6-membered nitrogen-containingheterocyclic ring.
 28. A compound of claim 24, wherein R³ is --SO₂ R⁴wherein R⁴ is an optionally substituted hydrocarbon group, --COR⁵wherein R⁵ is a hydrogen atom or an optionally substituted hydrocarbongroup, --COOR⁶ wherein R⁶ is an optionally substituted hydrocarbongroup) or --CON(R⁷)R⁸ wherein R⁷ and R⁸ respectively are a hydrogen atomor an optionally substituted hydrocarbon group, or R⁷ and R⁸ form a ringtogether with the adjacent nitrogen atom.
 29. A compound of claim 24,wherein ring Q is unsubstituted.
 30. A compound of claim 30, whereinring W is ##STR126##
 31. A compound of claim 30, wherein D is C₁₋₆alkylene.
 32. A compound of claim 24 represented by the formula: is 0,and the other symbols have the same meaning as defined in claim 30, or apharmaceutically acceptable salt thereof.
 33. A compound of claim 32,wherein R³ is --SO₂ R⁴ wherein R⁴ is an optionally substitutedhydrocarbon group, --COR⁵ wherein R⁵ is a hydrogen atom or an optionallysubstituted hydrocarbon group or --COOR⁶ wherein R⁶ is an optionallysubstituted hydrocarbon group.
 34. A compound of claim 33, wherein R⁴,R⁵ and R⁶ respectively are an optionally halogenated hydrocarbon group.35. A compound of claim 32, wherein D is C₁₋₆ alkylene.
 36. A compoundof claim 32, wherein D is ethylene.
 37. A compound of claim 32, whereinring W is ##STR127##
 38. A compound of claim 32, wherein R³ is --SO₂ R⁴wherein R⁴ is an optionally substituted hydrocarbon group.
 39. Acompound of claim 38, wherein R⁴ is an optionally halogenated C₁₋₆ alkylgroup.
 40. A compound of claim 32, wherein ring W is
 41. A compound ofclaim 32, wherein ring Q is unsubstituted.
 42. The compound1,2-dihydro-1-(1-trifluoromethanesulfonylpiperidin-4-ylmethyl)-1,4,7b-triazacyclopentcd!inden-2-one, or a pharmaceutically acceptable salt thereof.
 43. Thecompound 1,2-dihydro-1-2-(1-trifluoromethanesulfonylpiperidin-4-yl)ethane-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one, or a pharmaceutically acceptable salt thereof.
 44. Thecompound 1,2-dihydro-1-3-(trifluoromethanesulfonylpiperidin-4-yl)propan-1-yl!-1,4,7b-triazacyclopentcd!inden-2-one, or a pharmaceutically acceptable salt thereof.
 45. Aprocess for producing a compound of claim 1, which comprises reacting acompound of the formula wherein ring Q, R¹ and ring A are as defined inclaim 1, or a pharmaceuticallv acceptable salt thereof with a compoundof the formula:

    E.sup.1 --Y

wherein E¹ is a leaving group and Y is as defined in claim 1, or apharmaceutically acceptable salt thereof.
 46. A pharmaceuticalcomposition comprising an effective amount of the compound of claim 1 ina pharmaceutically acceptable carrier or diluent.
 47. A therapeuticcomposition for inhibiting platelet-derived growth factor, whichcomprises a! an effective amount of the compound of claim 1 in apharmaceutically acceptable carrier or diluent.
 48. A therapeuticcomposition for hypertension diseases, which comprises an effectiveamount of the compound of claim 1 in a pharmaceutically acceptablecarrier or diluent.
 49. A therapeutic composition for renal diseases,which comprises an effective amount of the compound of claim 1 in apharmaceutically acceptable carrier or diluent.
 50. A pharmaceuticalcomposition for lowering lipid level, which comprises an effectiveamount of the compound of claim 1 in a pharmaceutically acceptablecarrier or diluent.
 51. A compound of the formula: ##STR128## whereinR^(1a) and R^(1b) are each independently a halogen, an optionallysubstituted C₁₋₁₈ hydrocarbon selected from alkyl, cycloalkyl, alkenyl,aralkyl or aryl, or an acyl group, with the proviso that R^(1a) is notmethyl;R¹ is a hydrogen atom, a halogen atom, an optionally substitutedC₁₋₁₈ hydrocarbon group selected from an alkyl group, a cycloalkylgroup, an alkenyl group, an aralkyl group, or an aryl group, or an C₁₋₆acyl group; X¹ is an oxygen or a sulfur atom; ring Q is optionallysubstituted with one to three substituents selected from (i) halogenatom, (ii) alkyl group,(iii) halogeno-alkyl group, (iv) alkoxyl group,(v) halogeno-alkoxyl group, (vi) alkylthio group, (vii)halogeno-alkylthio group, (viii) hydroxyl group, (ix) carboxyl group,(x) cyano group, (xi) nitro group, (xii) amino group, (xiii) mono-alkylamino group, (xiv) di-alkyl amino group, (xv) formyl group, (xvi)mercapto group, (xvii) alkyl-carbonyl group, (xviii) alkoxyl-carbonylgroup, (xix) sulfonyl group, (xx) alkylsulfonyl group, (xxi) carbamoylgroup, (xxii) mono-alkyl-carbamoyl group, or (xxiii) di-alkyl-carbamoylgroup; with the proviso that when Q is substituted by more than onesubstituent selected from (ix) carboxyl group, (x) cyano group, (xi)nitro group, (xv) formyl group, (xvii) alkyl-carbonyl group, (xviii)alkoxyl-carbonyl group, (xix) sulfonyl group or (xx) alkylsulfonylgroup, these substituents are substituted in the meta position to eachother and there is a maximum of two of these substituents present onring Q; wherein when the hydrocarbon group is substituted, then thehydrocarbon group is substituted as follows:the alkyl, cycloalkyl, andalkenyl groups are substituted with one to five substituents selectedfrom the group consisting of (i) nitro group, (ii) hydroxyl group, (iii)cyano group, (iv) carbamoyl group, (v) mono-alkyl-carbamoyl group, (vi)di-alkyl-carbamoyl group, (vii) carboxyl group, (viii) alkoxyl-carbonylgroup, (ix) sulfonyl group, (x) halogen atom, (xi) alkoxyl group, (xii)phenoxy group, (xiii) halogenophenoxy group, (xiv) alkylthio group, (xv)mercapto group, (xvi) phenylthio group, (xvii) pyridylthio group,(xviii) alkylsulfinyl group, (xix) alkylsulfonyl group, (xx) aminogroup, (xxi) acylamino group, (xxii)mono-alkylamino group,(xxiii)di-alkylamino group, (xxiv) 4 to 6 member cyclic amino group,(xxv) acyl group, (xxvi) benzoyl group and (xxvii) 5 to 10 memberheterocyclic group; the aralkyl group is substituted with one to foursubstituents selected from the group consisting of (i) halogen atom,(ii) alkyl group, (iii) halogeno-alkyl group, (iv) alkenyl group, (v)acyl group (vi) alkoxyl group, (vii) nitro group (viii) cyano group,(ix) hydroxyl group, (x) alkoxyl-carbonyl group, (xi) carbamoyl group,(xii) mono-alkyl-carbamoyl group, (xiii) di-alkyl-carbamoyl (xiv) mono-alkenyl-carbamoyl group, and (xv) di-alkenyl-carbamoyl group; and thearyl group is substituted with one to four substituents selected fromthe group consisting of (i) halogen atom, (ii) alkyl group, (iii)halogeno-alkyl group, (iv) alkenyl group, (v) acyl group, (vi) alkoxylgroup, (vii) nitro group, (viii) cyano group, (ix) hydroxyl group, (x)alkoxyl-carbonyl group, (xi) carbamoyl group, (xii) mono-alkyl-carbamoylgroup, (xiii) di-alkyl-carbamoyl (xiv) mono-alkenyl-carbamoyl group,(xv) di-alkenyl-carbamoyl group and (xvi) oxo group; or apharmaceutically acceptable salt thereof.
 52. The compound of claim 1,wherein ring Q is optionally substituted with one to three substituentsselected from (i) halogen atom, (ii) C₁₋₄ alkyl group, (iii)halogeno-C₁₋₄ alkyl group, (iv) C₁₋₄ alkoxyl group, (v) halogeno-C₁₋₄alkoxyl group, (vi) C₁₋₄ alkylthio group, (vii) halogeno-C₁₋₄ alkylthiogroup, (viii) hydroxyl group, (ix) carboxyl group, (x) cyano group, (xi)nitro group, (xii) amino group, (xiii) mono-C₁₋₄ alkyl amino group,(xiv) di-C₁₋₄ alkyl amino group, (xv) formyl group, (xvi) mercaptogroup, (xvii) C₁₋₄ alkyl-carbonyl group, (xviii) C₁₋₄ alkoxyl-carbonylgroup, (xix) sulfo group, (xx) C₁₋₄ alkylsulfonyl group, (xxi) carbamoylgroup, (xxii) mono-C₁₋₄ alkyl-carbamoyl group, or (xxiii) di- C₁₋₄alkyl-carbamoyl group; with the proviso that when Q is substituted bymore than one substituent selected from (ix) carboxyl group, (x) cyanogroup, (xi) nitro group, (xv) formyl group, (xvii) C₁₋₄ alkyl-carbonylgroup, (xviii) C₁₋₄ alkoxyl-carbonyl group, (xix) sulfonyl group or (xx)C₁₋₄ alkylsulfonyl group. these substituents are substituted in the metaposition to each other and there is a maximum of two of thesesubstituents present on ring Q;R¹ is a hydrogen atom, a halogen atom, anoptionally substituted C₁₋₁₈ hydrocarbon group selected from a C₁₋₁₅alkyl group, a C₃₋₈ cycloalkyl group, a C₂₋₈ alkenyl group, a C₉₋₁₆aralkyl group, or a C₆₋₁₄ aryl group, or an C₁₋₆ acyl group; whereinwhen the hydrocarbon group of R¹ or R² is substituted, then thehydrocarbon group is substituted as follows:the alkyl, cycloalkyl,alkenyl and alkynyl groups are substituted with one to five substituentsselected from the group consisting of (i) nitro group, (ii) hydroxylgroup, (iii) cyano group, (iv) carbamoyl group, (v) mono-C₁₋₄alkyl-carbamoyl group, (vi) di-C₁₋₄ alkyl-carbamoyl group, (vii)carboxyl group, (viii) C₁₋₄ alkoxyl-carbonyl group, (ix) sulfonyl group,(x) halogen atom, (xi) C₁₋₄ alkoxyl group, (xii) phenoxy group, (xiii)halogenophenoxy group, (xiv) C₁₋₄ alkylthio group, (xv) mercapto group,(xvi) phenylthio group, (xvii) pyridylthio group, (xviii) C₁₋₄alkylsulfinyl group, (xix) C₁₋₄ alkylsulfonyl group, (xx) amino group,(xxi) C₁₋₃ l acylamino group, (xxii)mono-C₁₋₄ alkylamino group,(xxiii)di-C₁₋₄ alkylamino group, (xxiv) 4 to 6 member cyclic aminogroup, (xxv) C₁₋₃ acyl group, (xxvi) benzoyl group and (xxvii) 5 to 10member heterocyclic group; the aralkyl group is substituted with one tofour substituents selected from the group consisting of (i) halogenatom, (ii) C₁₋₄ alkyl group, (iii) halogeno-C₁₋₄ alkyl group, (iv)C2-4alkenyl group, (v) C₁₋₃ acyl group (vi) C₁₋₄ alkoxyl group, (vii)nitro group (viii) cyano group, (ix) hydroxyl group, (x) C₁₋₄alkoxyl-carbonyl group, (xi) carbamoyl group, (xii) mono-C₁₋₄alkyl-carbamoyl group, (xiii) di-C₁₋₄ alkyl-carbamoyl, (xiv) mono-C₂₋₄alkenyl-carbamoyl group, and (xv) di-C₂₋₄ alkenyl-carbamoyl group; andthe aryl group is substituted with one to four substituents selectedfrom the group consisting of (i) halogen atom, (ii) C₁₋₄ alkyl group,(iii) halogeno-C₁₋₄ alkyl group, (iv) C₂₋₄ alkenyl group, (v) C₁₋₃ acylgroup, (vi) C₁₋₄ alkoxyl group, (vii) nitro group, (viii) cyano group,(ix) hydroxyl group, (x) C₁₋₄ alkoxyl-carbonyl group, (xi) carbamoylgroup, (xii) mono-C₁₋₄ alkyl-carbamoyl group, (xiii) di-C₁₋₄alkyl-carbamoyl (xiv) mono- C₂₋₄ alkenyl-carbamoyl group, (xv) di-C₂₋₄alkenyl-carbamoyl group, and (xvi) oxo group; or a pharmaceuticallyacceptable salt thereof.
 53. The compound of claim 1, wherein said 4 to6 membered cyclic amino groups are selected from 1 azetidinyl,1-pyrrolidinyl, piperidino, morpholino, thiomorpholino or 1-piperazinyl.54. The compound of claim 1, wherein said 5 to 10 member heterocyclicgroups are selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-thiazolyl, 3-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 1,2,3 triazolyl, 1,2,4 triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl,quinolyl or isoquinolylindolyl.
 55. A pharmaceutical compositioncomprising an effective amount of the compound of claim 1 in apharmaceutically acceptable carrier or diluent.